TEXAPHYRIN METAL COMPLEX MEDIATED ESTER HYDROLYSIS

Abstract: A method of phosphate ester hydrolysis including incubating a solution of an aqueous phosphate ester with a texaphyrin metal complex. The metal is a metal cation having catalytic activity for ester bond hydrolysis in aqueous solution, in particular, a lanthanide metal cation, preferably Eu(III) or Dy(III). A preferred substrate is RNA and a preferred texaphyrin is a derivatized texaphyrin having binding specificity, in particular, a texaphyrin covalently coupled to a site-directed molecule, preferably an oligonucleotide.

Description: DESCRIPTION TEXAPHYRIN METAL COMPLEX MEDIATED ESTER HYDROLYSIS BACKGROUND OF THE INVENTION The present invention relates to catalysts for the cleavage of ester bonds, in particular, phosphate ester bonds related to a biological system. An effective catalyst would have the following properties: 1) Efficiency at physiological temperature and pH; 2) Specificity for certain biological substrates; 3) Low toxicity for physiological systems; and 4) Easy administration to a biological system and ready subsequent elimination. Various biologically important phosphate esters may be hydrolyzed according to the methods of the present invention, including RNA, phospholipids, phosphate anhydrides, UDP-glucose or a widely used substrate for assays, p-nitrophenylphosphate ester. Many divalent and trivalent metal salts have been shown to promote the hydrolysis of phosphate ester bonds. Komiyama et al. (1992) reported the hydrolysis of adenylyl(3'-5')adenosine and uridy1(3 '-5')uridine at pH 8.0, 30°C by rare earth metal(III) ions. A Cerium(III) hydroxide cluster has been reported to hydrolyze 3',5'- cyclic adenosine monophosphate (Sumao a, et al. 1992) . Browne and Bruice (1992) reported the hydrolysis of bis(8-hydroxyquinoline)phosphate in the presence of divalent cations. However, in order to convey a degree of specificity to catalysis by the metal ion, complexes of metals with various ligands have been studied. The ligand may serve a number of roles in catalysis including, modulation of catalytic efficiency, and maintenance of the metal ion in solution, while also allowing for coupling of reagents having a binding specificity for a desired substrate. Ligands complexing metal ions for use in the hydrolysis of phosphate ester bonds include: tris(a inopropyl)amine (trpn) , 1,4,7,10- tetraazacyclododecane (cyclen) , tris(2-aminoethyl)amine (tren) , triethylenetetramine (trien) , tetraethylenepentamine (tetren) , bipyridine conjugates, imidazole, cyclodextrin derivatives, lysine, terpyridine (trpy) , 1,2-diaminoethane, a bis(diaquo) complex, "metallomicelles" and a phenanthroline-polyamine tridentate complex (Basile et al. 1987, Menger et al . 1987, Chung et al . 1990, Hendry and Sargeson, 1989, SheIton and Morrow, 1991, Ranganathan et al. 1993, Breslow and Huang, 1991, Modak et al . 1991, Kim and Chin, 1992, Chin et al . 1989, Chin and Banaszczyk, 1989a,b, Chin and Zou, 1987) . In order for a metal complex to function catalytically in vivo, the complex should not release bound metal ion. Morrow et al . (1992) have studied the cleavage of RNA by a lanthanide(III) hexamine Schiff-base (HAM) macrocyclic complex. Cleavage of the dinucleotide adenylyl-3',5'uridine 3'-monophosphate (ApUp) or of oligomers of adenylic acid (A12-A18) was reported at 37°C after 4 hours by several lanthanide complexes. Other hexadentate ligands such as EDTA formed lanthanide(III) complexes that are completely inactive in RNA cleavage under similar conditions. Inertness of the macrocyclic complex to metal release was reported to change dramatically throughout the lanthanide series. These complexes have some serious disadvantages, including high toxicity of the HAM ligand, weak coordination and dissociation of the lanthanide metals. Further, the ligand cannot be easily modified which precludes the generation of derivatives with substrate specificity. Given the limitations of the HAM complex, it is clear that the development of new macrocycles, capable of chelating lanthanide metals and forming stable complexes which are able to cleave RNA, would be of utility. LIST OF ABBREVIATIONS DEPC Diethylpyrocarbonate dm decimeter EDTA Ethylenediamine tetraacetic acid EuOAc Eu(III) (acetate)3 Txp(txph) (TX) Texaphyrin SUMMARY OF THE INVENTION The present invention seeks to solve these problems by providing texaphyrin metal complexes and texaphyrin metal complex-conjugates for ester hydrolysis that provide stable chelation for an otherwise toxic metallic cation, specificity for targeted sites in a therapeutic application, and sufficient nontoxicity for in vivo use. The present invention involves the discovery that texaphyrin metal complexes catalyze the hydrolysis of ester linkages. Texaphyrins are unique molecules in that they chelate the metal in a very stable complex but allow access to the metal coordination sites, thus preserving the metal's reactivity and its ability to hydrolyze phosphoester bonds. Furthermore, the texaphyrin molecule allows for derivatization for various biological applications. The texaphyrin complex is far less toxic than the HAM complex as well. U.S. Patent 5,252,720, incorporated herein by reference, demonstrated the stability and utility of texaphyrin metal complexes for in vivo use in magnetic resonance imaging protocols. The Y^ + , Gd + , and I * + complexes of texaphyrin were found to be hydrolytically stable in 1:1 methanol-water mixtures with half-lives for deσomplexation and/or ligand decomposition exceeding 3 weeks in both cases. A T2B2 texaphyrin-gadolinium complex showed low toxicity and good tissue selectivity in magnetic resonance imaging enhancement. The texaphyrin metal complex-conjugates of the present invention are expected to have similar stability for chelating lanthanide metal cations and similar low toxicity for in vivo applications. Texaphyrin metal complexes possess inherent biolocalization specificity as described in the '720 patent. In one embodiment of the present invention, the texaphyrin metal complexes are further coupled to site- directed molecules to form conjugates for targeted in vivo delivery. "Specificity for targeted sites" means that upon contacting the texaphyrin metal complex- conjugate with the targeted site, for example, under physiological conditions of ionic strength, temperature, pH and the like, specific binding will occur. The interaction may occur due to specific electrostatic, hydrophobic, entropic or other interaction of certain residues of the conjugate with specific nucleotide, amino acid or glycolytic residues of the target to form a stable complex under the conditions effective to promote the interaction. In the present invention, this interaction will allow cleavage of an ester linkage that is in the vicinity of the specific binding. Exemplary site-directed molecules contemplated in the present invention include but are not limited to: polynucleotides and oligonucleotides such as antisense oligonucleotides; polyamides including peptides having affinity for a biological receptor and proteins such as antibodies; steroids and steroid derivatives; hormones such as estradiol, morphine or histamine; and further macrocycles such as sapphyrins and rubyrins. It is understood that the terms "nucleotide", "polynucleotide" and "oligonucleotide", as used herein and in the appended claims, refer to both naturally- occurring and synthetic nucleotides, poly- and oligonucleotides and to analogs and derivatives thereof. Hydrolytic cleavage of RNA by lanthanide(III) texaphyrins may be enhanced by additional catalytic groups appended to the texaphyrin metal complex- conjugate. The term "additional catalytic groups" means chemical functional groups that assist catalysis by acting as a general acid, Brønsted acid, general base, Brønsted base, nucleophile, or any other means by which the activation barrier to reaction is lowered or the ground state energy of the substrate is increased. Exemplary catalytic groups contemplated in the present invention include, but are not limited to, imidazole; guanidine; substituted saccharides such as D-glucosamine, D-mannosamine, D-galactosamine, D-glucamine and the like; amino acids such as L-histidine and L-arginine; derivatives of amino acids such as histamine; polymers of amino acids such as poly-L-lysine, (LysAla) n , (LysLeuAla) n where n is from 1-30 or preferably 1-10 or most preferably 2-7, and the like, derivatives thereof and texaphyrin metal complexes. The term "appended to the texaphyrin metal complex-conjugate" means that the catalytic groups are attached either directly to the texaphyrin metal complex via a linker or couple of variable length, or attached to the ligand portion of a texaphyrin com lex-ligand conjugate. For example, a catalytic group attached to the oligonucleotide portion of a texaphyrin metal complex-oligonucleotide conjugate is placed in the vicinity of the substrate upon binding the targeted RNA substrate. A conjugate group having site specificity or catalytic activity may be covalently coupled to a texaphyrin directly on the macrocycle ring or through various couples. A couple may be described as a linker, i.e. a reactive group for covalently attaching another molecule at a distance from the texaphyrin macrocycle. Exemplary linkers or couples are amides, thiols, thioether or ether covalent bonds as described in the examples for attachment of oligonucleotides and antibodies. In most preferred embodiments, conjugates and appended groups are covalently bonded to the texaphyrin via a carbon-carbon, a carbon-nitrogen or a carbon-oxygen bond. It will be apparent to one of skill in the art in light of the present disclosure that a variety of ester linkages may be cleaved by the molecules of the present invention. Exemplary ester linkages cleaved by the molecules of the present invention include phosphate monoester and diester linkages, especially physiologically important phosphate linkages present in nucleic acids such as RNA; important mediators of metabolism such as nucleotides ATP, ADP, AMP, cAMP, UDP, NADH, NADPH, FAD or FADH 2 , for example; and phospholipids such as phosphatidyl choline and sphingomyelin that are important in nerve and brain functions. An embodiment of the present invention provides a method of phosphate ester hydrolysis. The method comprises the steps of obtaining an aqueous phosphate ester solution, and incubating the solution with a texaphyrin metal complex having catalytic activity for ester bond hydrolysis, the incubation being under conditions and for a time sufficient to hydrolyze the phosphate ester. A texaphyrin metal complex as used herein is an aromatic pentadentate expanded porphyrin analog metal complex with appended functional groups. Such pendant groups may enhance solubility or biolocalization or may provide coupling sites for site- directed molecules or catalytic groups. The metal is a divalent or a trivalent metal cation having catalytic activity for ester bond hydrolysis in aqueous solution, in particular, the metal is a lanthanide cation or a Lewis acidic cation such as Y(III), In(III), or Sc(III). Exemplary, metals include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium or yttrium. In particular, the metal may be La(III), Nd(III), Sm(III) , Gd(III), Tm(III) , or Lu(III) , or preferably, Eu(III) or Dy(III) . In a preferred embodiment, the phosphate ester is a nucleic acid ester. The aqueous phosphate ester solution may be a solution or a suspension of nucleic acid, for example, a solution or suspension of RNA or DNA. RNA is more preferably hydrolyzed than DNA by a factor of about 10* . hen the phosphate ester is RNA, the metal is preferably Dy(III) or Eu(III) . The texaphyrin metal complex may be a water soluble compound having the structure: In this texaphyrin metal complex, M is a divalent or a trivalent metal cation catalyzing ester bond hydrolysis in aqueous solution. R j , R 2 , R3, R4, R5 and g are independently hydrogen, hydroxy1, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, saccharide, carboxyalky1, carboxyamidealky1, a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group. A site-directed molecule is the conjugate of a texaphyrin metal complex-conjugate. A catalytic group is also the conjugate of a texaphyrin metal complex-conjugate and may include, but is not limited to, imidazole, guanidine or texaphyrin. N will typically be an integer less than or equal to 2. In the context of the basic macrocycle with a divalent or trivalent metal cation, N is 1 or 2; however, with a site-directed molecule covalently attached, one skilled in the art in light of the present disclosure would realize that the value of N would be altered due to charges present on the site-directed molecule, for example, charges of the phosphate groups on an oligonucleotide. R j , R 2 , R3, R 4 , 5 and Rg may also independently be amino, carboxy, carboxamide, ester, amide sulfonato, aminoalkyl, sulfonatoalkyl, amidealkyl, aryl, etheramide or equivalent structures conferring the desired properties. In a preferred embodiment, at least one of j , R 2 , R3, R 4 , R5 and g is a site-directed molecule or is a couple to a site-directed molecule. For bulky R groups on the benzene ring portion of the molecule such as antibodies, peptides or oligonucleotides, one skilled in the art would realize that derivatization at one position on the benzene portion is more preferred. Hydroxyalkyl means alkyl groups having hydroxyl groups attached. Alkoxy means alkyl groups attached to an oxygen. Hydroxyalkoxy means alkyl groups having ether or ester linkages, hydroxyl groups, substituted hydroxyl groups, carboxy1 groups, substituted carboxyl groups or the like. Saccharide includes oxidized, reduced or substituted saccharide. Carboxyamidealkyl means alkyl groups with hydroxyl groups, secondary or tertiary amide linkages or the like. Carboxyalkyl means alkyl groups having hydroxyl groups, carboxyl or amide substituted ethers, ester linkages, tertiary amide linkages removed from the ether or the like. For the above-described texaphyrins, hydroxyalkoxy may be alkyl having independently hydroxy substituents and ether branches or may be or OC/ n . x ) H (( 2n+l ) -2x ) °x° y where n is a positive integer from 1 to 10, x is zero or a positive integer less than or equal to n, and y is zero or a positive integer less than or equal to ((2n+l)-2x). The hydroxyalkoxy or saccharide may be 0C n H ((2n+l)-q)°y Ra q ° r ( CH 2)n C0 2 Ra where * is a positive integer from 1 to 10,y is zero or a positive integer less than ((2n+i)-q), q is zero or a positive integer less than or equal to 2n+l, and R a is independently H, alkyl, hydroxyalkyl, saccharide, c (m-w) H ((2m+l)-2w)°w°z' 0 2 cc (m-w) H ((2m+l)-2w)°w°z or N(R)OCC (m . w) H ((2m+1) . 2w) θ w O z . In this case, m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to , z is zero or a positive integer less than or equal to ((2m+l)-2w), and R is H, alkyl, hydroxyalkyl, or where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+l)-r), r is zero or a positive integer less than or equal to 2m+l, and R b is independently H, alkyl, hydroxyalkyl, or saccharide. Carboxyamidealkyl may be alkyl having secondary or tertiary amide linkages or (CH 2 ) n CONHR a , 0(CH 2 ) n CONHR a , (CH 2 ) n CON(R a ) 2 , or 0(CH 2 ) n CON(R a ) 2 where n is a positive integer from 1 to 10, and R a is independently H, alkyl, hydroxyalkyl, saccharide, C (m . w) H ((2m+ i).2 w )°w°z > °2 cc (m-w) H ((2m+l)-2w) 0 w°z' N ( R > 0CC (m-w) H ((2m+l)-2w) 0 w°z' or a site-directed molecule or catalytic group. In this case, m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+l)-2w), and R is H, alkyl, hydroxyalkyl, or c m H ((2m+ i ) . r) O z R' ) r . In this case, m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+l)-r), r is zero or a positive integer less than or equal to 2m+l, and R" is independently H, alkyl, hydroxyalkyl, or saccharide. In a preferred embodiment, R a is an oligonucleotide. Carboxyalkyl may be alkyl having a carboxyl substituted ether, an amide substituted ether or a tertiary amide removed from an ether or C n H 2n+ i ) - π) 0yR C q or 0C n H (( 2n+D- q ^ y ^ q where n is a positive integer from 1 to 10; y is zero or a positive integer less than ((2n+l)-q), q is zero or a positive integer less than or equal to 2n+l, and R c is (CH 2 ) n C0 2 R d , (CH 2 ) n CONHR d , (CH 2 ) n CON(R d ) 2 or a site-directed molecule or catalytic group. In this case, n is a positive integer from 1 to 10, R" is independently H, alkyl, hydroxyalkyl, saccharide, C m . w) H ((2m+l)-2w)°w°z' °2 CC (m-w) H ((2m+l)-2w)°w°z or N(R) 0 CC (m . w) H ((2m+l)-2w)°w°z* In tn:LS case, m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+l)-2w), and R is H, alkyl, hydroxyalkyl, or C m H ((2m+l)-r)°z Rt r* In tn i s case, m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+l)-r) , r is zero or a positive integer less than or equal to 2m+l, and R b is independently H, alkyl, hydroxyalkyl, or saccharide. In a preferred embodiment, R c is an oligonucleotide. In an embodiment of the present invention, M may be a divalent metal cation selected from the group consisting of Ca +2 , Mn +2 , Co "1"2 , Ni +2 , Zn +2 , Cd +2 , Hg +2 , Fe +2 , Sm +2 and U0 +2 or a trivalent metal cation selected from the group consisting of Mn + , Co + , Ni + , Fe +3 , Ho +3 , Ce +3 , Y +3 , In +3 , Pr +3 , Nd +3 , Sm +3 , Eu +3 , Gd +3 , Tb +3 , Dy +3 , Er +3 , Tm +3 , Yb +3 , Lu +3 , La +3 , and U +3 . In presently preferred texaphyrins, R j is hydroxyalkyl and R 2 , R 3 and R are alkyl. Alternatively, R3 may be a site-directed molecule or a couple to a site- directed molecule, preferably an oligonucleotide or a couple to an oligonucleotide. In a further preferred texaphyrin, R j is (CH 2 ) 2 CH 2 OH, R 2 and R3 are CH 2 CH 3 , R 4 is CH3 and R5 and Rg are OCHCH 2 CH 2 OH. Alternatively, R5 is a site-directed molecule or a couple thereto, preferably an oligonucleotide or a couple thereto, more preferably 0(CH 2 ) n CO-oligonucleotide where n is 1-7 and preferably 1- 3; and Rg is H. In a further presently preferred embodiment, R j is (CH 2 ) 2 CH 2 OH, R 2 and R 3 are CH 2 CH 3 , R 4 is CH3, R 5 is 0(CH 2 CH 2 0) 2 CH 2 CH 2 OCH3 and Eg is a site-directed molecule or a couple thereto, preferably an oligonucleotide or a couple thereto, more preferably 0(CH 2 ) n CO-oligonucleotide where n is 1-7 and preferably 1- 3. In other presently preferred embodiments, R j -Rg are as in Table 1 for texaphyrins A1-A29. In a further embodiment of the present invention, at least one of R j , R 2 , R3, R 4 , R5 and Rg is a site-directed molecule or is a couple to a site-directed molecule. In a more preferred embodiment, the site-directed molecule is an oligonucleotide or is a couple to an oligonucleotide and most preferably, the oligonucleotide is a deoxyribonucleotide and the phosphate ester to be cleaved is RNA. The oligonucleotide has complementary binding affinity for the RNA in a region proximal to the phosphate ester bond being hydrolyzed. The oligonucleotide may have complementary binding affinity for viral RNA, in particular, retroviral RNA, or for bacterial ribosomal RNA, thereby cleaving the viral RNA or bacterial RNA and killing the organism. When the phosphate ester is RNA, the metal cation is preferably a lanthanide metal cation, more preferably, Eu(III) or Dy(III). The oligonucleotide may be a deoxyribonucleotide and have complementary binding affinity for oncogenes. The oligonucleotide, antibody, hormone, sapphyrin or rubyrin may have binding specificity for localization to a treatment site and the biological receptor may be localized to a treatment site. Another embodiment of the present invention is a method of phosphate ester hydrolysis comprising the steps of i) obtaining an aqueous phosphate ester solution and ii) incubating the solution with a texaphyrin metal complex linked to a sapphyrin. Sapphyrins have binding specificity for phosphate esters as described in Example 12. The incubation is under conditions and for a time sufficient to hydrolyze the phosphate ester. Sapphyrin compounds are disclosed in U.S. Patents 5,159,065 and 5,120,411, incorporated by reference herein. Another embodiment of the present invention is a method for targeted intracellular mRNA hydrolysis. The method comprises the introduction into a cell of a texaphyrin metal complex coupled to an oligonucleotide having complementary binding affinity for a targeted RNA, whereby hydrolysis of the targeted mRNA is catalyzed by the texaphyrin metal complex. The mRNA may be transcribed from an oncogene or it may encode a growth factor, for example. The mRNA may be a normal mRNA which needs to be destroyed, for example, due to improper timing of expression. A method for inhibiting the expression of a gene in an animal comprising the administration to the animal of a texaphyrin metal complex-conjugate is a further embodiment of the present invention. The oligonucleotide may have complementary binding affinity for messenger RNA transcribed from said gene or may be complementary to either strand of the DNA surrounding the gene or encoding the gene. The gene may be an oncogene or it may encode a growth factor, for example. A further embodiment of the present invention is a method for inhibiting the expression of a gene in a particular tissue of an animal comprising administering to the animal a texaphyrin metal complex-conjugate having specificity for the tissue. The texaphyrin metal complex-conjugate may have appended an oligonucleotide complementary to the target gene and a further appended tissue-specific molecule like estradiol, for example, or an antibody directed for said tissue or a peptide having affinity for a biological receptor on said tissue. A further embodiment of the present invention is a texaphyrin metal complex-conjugate wherein two or more separate texaphyrin complexes are attached to an oligonucleotide, one at the 3', one at the 5' end and one or more at an internal residue. The metal ion of each of the texaphyrin complexes may be the same or it may be different and is preferably a lanthanide ion. Use of a dual texaphyrin complex-conjugate should effect the hydrolysis of RNA with increased efficiency due to the concerted activity of the metal complexes. For diagnosis and treatment purposes, the administration of such a conjugate with one texaphyrin complex having an ester bond-hydrolyzing metal species and the other having a paramagnetic species would allow binding, imaging and hydrolysis, all effected by one conjugate. In this case, binding is effected by the oligonucleotide, imaging is accomplished by MRI or fluorescence microscopy due to the presence of the paramagnetic metal ion and hydrolysis is accomplished by the ester bond-hydrolyzing metal species. Therefore, the biodistribution and cellular penetration of the conjugate may be determined. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1C schematically summarize the synthesis of B2T2TXP(1 H , l j ) and lanthanide metal complexes of B2T2, l j -l w . Figures 2A-2B schematically summarize the synthesis of an oligonucleotide conjugate of a texaphyrin metal complex, 2JJ. Figures 3A-3C demonstrate the covalent coupling of texaphyrin metal complexes with amine, thiol or hydroxy linked oligonucleotides to form preferred compounds of the present invention. Figures 4A-4D demonstrate the synthesis of diformyl monoacid tripyrrane 4JJ and oligonucleotide conjugate . Figure 5 shows the recombinant plasmid from which J *p-labelled 2000 base pair RNA transcripts were made for the RNA hydrolysis experiments of Example 6. Rl = JSσoRI, MCS = multi-cloning sequence. Figure 6 shows the autoradiogram of control experiments where RNA transcripts were incubated with europium acetate and with EuOAc and EDTA. Lane 1, control , no EuOAc; lane 2, control with EDTA, no EuOAc; lanes 3-7, EuOAc, 100 μM, 50 μM, 25 μM, 10 μM, and 5 μM; lane 8, EuOAc, 100 μM and EDTA 500 μM; lane 9, EuOAc, 100 μM and EDTA, 300 μM; lane 10, EuOAc, 100 μM and EDTA, 100 μM; lane 11, EuOAc, 100 μM and EDTA, 10 μM; lane 12, MW std; lane 13, control, no EuOAc; lane 14, MW std. Figure 7 shows the autoradiogram of experiments where RNA transcripts were incubated with europium B2T2 txph. Lane 1, control, no EuB2T2 txph; lane 2, control with EDTA; lanes 3-7, EuB2T2 txph, 100 μM, 50 μM, 25 μM, 10 μM and 5 μM; lanes 8-10, EuB2T2 txph, 100 μM and EDTA at 500 μM, 300 μM and 100 μM; lane 11, M.W. std; lane 12, control, no EuB2T2 txph; lane 13, EuB2T2 txph, 100 μM and EDTA, 10 μM. Figure 8 shows presently preferred texaphyrin- europium complexes of the present invention. Figure 9 shows europium (III) texaphyrin (EuTx) DNA conjugates of Example 7, dysprosium (III) texaphyrin (DyTx) conjugates of Example 8, oligonucleotides conjugated at the 3' end to texaphyrin and dual conjugates, i.e., oligonucleotides having a texaphyrin conjugated to the 5' and to the 3' end. Oligonucleotides are written in a 5' — 3 ' direction. Figure 10 shows a schematic representation of cleavage of an RNA 31-mer by EuTx-DNA conjugate and of an RNA 36-mer by Dy-Tx-DNA conjugate; the arrows show sites of metal-catalyzed hydrolysis. Figures 11A and 11B show cleavage of synthetic RNA 30-mer 10 B by EuTx-DNA conjugates or free europium complex 8g. Autoradiograph of a 20% high resolution denaturing polyacrylamide gel labelled with 2 P at the 3 ' end. Ca. 1.5 X 10^ cpm of substrate was incubated for ca. 24h at 37°C in a total volume of 20 μL of buffer containing 50 mM HEPES, pH 7.5, 100 mM NaCl, 25 μM EDTA and 5 μg/mL calf thymus DNA. Key: lane 1, no DNA control; lane 2, control with unmodified oligodeoxynucleotide 9 E ; lane 3, 2.5μM 8 β ; lane 4, 25 μM 8 β ; lanes 5-7, 9 E and 250 nM, 2.5 μM, and 25 μM 8 β , respectively; lane 8, 9^; lane 9, 9^.; lane 10, 9g; lanes 11-14, 9 D at 2.5 nM, 25 nM, 250 nM, and 2.5 μM, respectively. All other oligonucleotides were at 2.5 μM final concentration. Nucleotide sequence analysis was determined by partial digestion with base-specific ribonucleases: T1(G); U2 (A>G) ; Phy M (U+A) ; B, cereus (U+C) ; HCO3 (alkaline hydrolysis) ; PNK (polynucleotide kinase-treated HCO3 lane) . Figure 12 shows cleavage of 5' end labelled RNA 30- mer 10 jj by EuTx-DNA conjugate 10 A (9 D ) . Labelled substrate was incubated with 2.5 μM EuTx-DNA conjugate for 24h at 37°C (lanes 3-6) or 25°C (lanes 7-14) in buffers containing 100 mM NaCl. Key: lane 1, non- incubated RNA control; lane 2, ribonuclease Tl (G) reaction; lanes 3, 8, 50 mM HEPES, pH 7.5, 25 μM EDTA; lanes 4, 9, 50 mM HEPES, pH 7.0, 25 μM EDTA; lane 5, 10:50 mM TrisAcetate pH 7.5, 25 μM EDTA; lanes 6,11,14, 50 mM TrisAcetate pH 7.0, 25 μM EDTA; lane 7, 50 mM HEPES, pH 7.5; lanes 12, 13, 50 mM TrisAcetate, pH 7.0; lane 13, 5 μM Fe(II), 4mM DTT, 5 μM non-modified oligo 9 j .; lane 14, no conjugate control. EuTx: conjugate- derived cleavage; Bkgd: background autocleavage. Figure 13 shows cleavage of 5'- end labelled RNA 30- mer IOJJ by EuTx-DNA conjugate 10 A (9p) . Labelled substrate was incubated for 25h at 37°C in 50 μm HEPES (or TrisAcetate, lane 6) buffer containing 100 mM NaCl, 25 μM EDTA, and 5 μg/mL calf thymus DNA. Key: lane 1, no DNA control; lane 2, non-modified oligodeoxynucleotide 9g (2.5 μM) ; lane 3, 9 β (2.5 μM) ; lane 4, 9 C (2.5 μM) ; lanes 5-9, 9 D (10 A ) (250 nM) . EuTx: conjugate-derived cleavage; Bkgd: background autocleavage. Figure 14 shows the hydrolysis of cUMP to uridine in the presence of EuTXP. Figure 15 shows the formation of amide linked derivatives of texaphyrin: R - sapphyrin, texaphyrin, porphyrin or a catalytic group; (NH 2 ) m represents monoamines NH 2 (CH 2 ) X , x=0-12; dia ines NH 2 -(CH 2 ) X -NH 2 , x=2- 12; triamines (NH 2 (CH ) χ )3N, x=2-6; or tetramines (NH 2 (CH 2 ) χ ) 2 N(CH 2 ) y N((CH 2 ) χ NH 2 ) 2 , X=2-4, y=2-6. Figure 16 shows the synthesis of a texaphyrin- sapphyrin conjugate, R may be H, OH, alkyl, hydroxyalkyl or alkoxy, M = Ln and n = 1-5. Figure 17 shows a dimer or conjugate of texaphyrins. The metals may be the same or different. Figures 18A and 18B show examples of the oligonucleotide conjugate having a one base deletion and, therefore, causing the substrate to have a one-base loop with enhanced susceptibility to hydrolysis. Figures 19A-19B schematically summarize the synthesis of a dysprosium texaphyrin having an imidazole catalytic group. Figures 20A-20B show europium texaphyrins having a histamine group attached (20A) and an arginine methyl ester group attached (2OB) . Figure 21 shows the use of a set of texaphyrin metal complex-conjugates targeted for the same hydrolysis site on the RNA template. Figure 22 shows cleavage of 5'-end. labelled RNA 30- mer IOJJ (lanes 1-9) or 36-mer 10 D (lanes 12-18) by EuTx- conjugates 9 B and 9 D or DyTx-conjugates 9 j and 9 H . Autoradiograph of a 20% denaturing polyacrylamide gel. Labelled substrate was incubated with or without 250nM conjugate for 24h at 37°C in buffer containing lOOmM NaCl, 50mM HEPES pH 7.5, 25μM EDTA. Key: lanes 1, 12, no conjugate control; lanes 2, 6, 13, 9 β ; lanes 3, 7, 14, 9 D ; lanes 4, 8, 15, 9 j ; lanes 5, 9, 16, 9 H ; lanes 10, 17, HCO3 sequencing; lanes 11, 18, base-specific ribonuclease U2 (A) sequencing. Reactions corresponding to lanes 1-5 were conducted under inert (argon) atmosphere, while reactions corresponding to lanes 12-16 were conducted under oxygen. LnTx, conjugate-derived cleavage; Bkgd, background autocleavage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention involves the use of texaphyrin metal complexes, in particular, water soluble texaphyrin metal complexes for the hydrolytic cleavage of ester bonds. More particularly, the invention involves the cleavage of phosphate ester bonds of a diester, a monoester and an RNA substrate using a lanthanide metal complex of a hydroxylated texaphyrin. Although a survey of lanthanide (III) texaphyrin complexes indicates that all of the metal complexes examined are capable of hydrolytically cleaving RNA, complexes of europium (III) and dysprosium (III) cleave RNA faster than other lanthanides of those tested thus far. An individual skilled in the art of organic synthesis in light of the present disclosure is able to prepare a large variety of lanthanide texaphyrins, all of which are expected to hydrolytically cleave phosphate esters, an important biological species. Potential particular applications for this process include the specific cleavage and possible subsequent recombination of RNA, destruction of viral RNA, digestion of cell membrane components such as phosphatidyl cholines and sphingomyelin, disruption of the transfer of free energy in cells by hydrolyzing ATP, ADP, NADH, NADPH, FAD or FADH 2 , treatment of liver diseases by preventing the formation of glycogen, regulation of hormones by hydrolysis of cAMP, hydrolysis of mutagenic and carcinogenic di- and trialkyl phosphates commonly used as solvents, and the detoxification of phosphate ester nerve gases and insecticides by hydrolysis of phosphate ester bonds. Texaphyrin compounds and methods for making are described in U.S. Patents 4,935,498, 5,162,509, 5,252,720, 5,272,142 and 5,256,399, each of which is incorporated by reference herein. Generally, the introduction of hydroxy substituents on the B (benzene ring) portion of the texaphyrin molecule is accomplished by their attachment to phenylenediamine in the 4 and 5 positions of the phenyl subunit of the molecule or they may be added in a synthetic step following the condensation step that forms the macrocycle metal complex as described in the above- named patents. The introduction of hydroxy substituents on the T (tripyrrole or tripyrrane) portion of the molecule is accomplished by appropriate functionalization of the alkyl substituents in the 3 and/or 4 positions of the pyrrole rings at a synthetic step prior to condensation with the substituted phenylenediamine. Standard deprotection methodology such as ester hydrolysis may be used to unmask free hydroxyl substituents. Alternatively, they may be prepared as the result of ester reduction. These derivatives exhibit significant solubility in aqueous media, up to 1 mM or better, yet they retain affinity for lipid rich regions which allows them to be useful in biological environments. Divalent and trivalent metal complexes of texaphyrins are by convention shown with a formal charge of N + , where N=l or 2, respectively. It is understood by those skilled in the art that the complexes described in the present invention have one or more additional ligands providing charge neutralization and/or coordinative saturation to the metal ion. Such ligands include chloride, nitrate, acetate, and hydroxide, among others. Exemplary texaphyrins of the present invention are listed in Table 1. TABLE 1. Representative Substituents for Texaphyrin Macrocycles of the Present Invention TABLE 1. - CONTINUED TABLE 1. - CONTINUED Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Unless mentioned otherwise, the techniques employed herein are standard methodologies well known to one of ordinary skill in the art. EXAMPLE 1 Synthesis of B2T2 TXP, see Fig. lA-lC. 2 , 5-Bis [ ( 5 -benzyloxy carbonyl -4 -methyl -3 -methoxycar- bonylethylpyrrol-2-yl) methyl] -3, 4-diethylpyrrole . I Q , Fig. IA. In a 500 mL round bottom flask was placed 250 mL of ethanol from an unopened bottle and this was then purged with dry nitrogen for ten minutes. 3,4-Diethylpyrrole 1 B (1.29 g, 0.01 mol) and 2-acetoxymethyl-5-benzyloxycarbonyl-4-methyl-3- methoxycarbonylethylpyrrole 1^ (7.83 g, 0.02 mol) were added and the mixture heated until all of the pyrroles dissolved. p-Toluenesulfonic acid (65 mg) was added and the reaction temperature maintained at 60° C. The reaction slowly changed color from a clear yellow to a dark red with the product precipitating out of the solution as the reaction progressed. After ten hours the reaction was cooled to room temperature, the volume reduced to one half on a rotary evaporator, and then placed in the freezer for several hours. The product was collected by filtration, washed with a small amount of cold ethanol to afford 4.61 g of an off white fine powder (61%): *H NMR (CDC1 3 , 250 MHz): δ 1.14 (6H, t, CH 2 Cff 3 ) , 2.23 (6H, s, pyrrole-Cff 3 ) , 2.31 (4H, t, CH 2 CH 2 C0 2 CH 3 ) , 2.50 (4H, q, CH 2 CH 3 ) , 2.64 (4H, t, CH 2 Cff 2 C0 2 CH 3 ) , 3.60 (10H, br s, Cff 3 C0 2 - and (pyrrole) 2 -CH 2 ) , 4.44 (4H, br s, C 6 H 5 Ci 2 ) , 6.99-7.02 (4H, , aromatic), 7.22-7.26 (6H, m, aromatic), 8.72 (IH, S, NH) , 10.88 (2H, br s, NH) ; 13 C NMR (CDCI3, 250 MHZ) : δ 10.97, 16.78, 17.71, 19.40, 22.07, 35.09, 51.46, 65.32, 117.37, 119.34, 122.14, 126.58, 126.79, 127.36, 128.19, 133.55, 136.62, 162.35, 173.49; Cl MS (M+H) + 750; HRMS 749.3676 (calc. for C 44 H 51 N 3 0g: 749.3676) . 2,5-Bis[ (5-benzyloxycarbonyl-3- (3 -hydroxy propyl) - 4-methylpyrrol-2yl) methyl] -3 , 4 -diethyl pyrrole . 1 D , Fig.lA. 2,5-Bis[ (5-benzyloxycarbonyl-4-methyl-3- methoxycarbonylethylpyrrol-2-yl)methyl]-3,4-diethylpyrrol e I Q (5.00 g, 0.007 mol) was placed in a three necked 100 mL round bottom flask and vacuum dried for at least 30 minutes. The flask was equipped with a thermometer, an addition funnel, a nitrogen inlet tube, and a magnetic stir bar. After the tripyrrane was partially dissolved into 10 mL of dry THF, 29 mL of borane (1M BH3 in THF) was added dropwise with stirring. The reaction became mildly exothermic and was cooled with a cool water bath. The tripyrrane slowly dissolved to form a homogeneous orange solution which turned to a bright fluorescent orange color as the reaction went to completion. After stirring the reaction for one hour at room temperature, the reaction was quenched by adding methanol dropwise until the vigorous effervescence ceased. The solvents were removed under reduced pressure and the resulting white solid redissolved into CH 2 C1 2 . The tripyrrane was washed three times with 0.5M HCl (200 mL total), dried over anhydrous K 2 C03, filtered, and the CH 2 C1 2 removed under reduced pressure until crystals of the tripyrrane just started to form. Hexanes (50 mL) was added and the tripyrrane allowed to crystallize in the freezer for several hours. The product was filtered and again recrystallized from CH 2 C1 2 /ethanol. The product was collected by filtration and vacuum dried to yield 3.69 g of an orangish white solid (76%): mp 172-173° C; *H NMR (CDCI3, 300 MHz): CJ 1.11 (6H, t, CH 2 Cff 3 ) , 1.57 (4H, p, CH 2 CH 2 CH 2 0H) , 2.23 (6H, s, pyrrole-CH 3 ) , 2.39-2.49 (8H, m, Cff 2 CH 3 and CH 2 CH 2 CH 2 0H) , 3.50 (4H, t, CH 2 CH 2 Cff 2 OH) , 3.66 (4H, S, (pyrrole) 2 -CH 2 ) , 4.83 (4H, s, C 6 H 5 -CH 2 ) , 7.17-7.20 (4H, m, aromatic), 7.25-7.30 (6H, m, aromatic), 8.64 (IH, s, NH) , 9.92 (2H, s, NH) ; 13 C NMR (CDCI3, 300 MHz): δ 10.97, 16.72, 17.68, 20.00, 22.38, 33.22, 62.01, 65.43, 117.20, 119.75, 120.72, 122.24, 127.23, 127.62, 128.30, 132.95, 136.60, 162.13; FAB MS (M + ) 693. 2, 5-Bis[ (3- (3 -hydroxy propyl) -5-carboxyl-4- methylpyrrol-2-yl) methyl] -3 , 4-diethylpyrrole l β , Fig. IB . 2,5-Bis[ (3-(3-hydroxypropyl)-5-benzyloxycarbonyl-4- methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole 1 D (15.0 g, 0.02 mol) was placed in a 1 L round bottom flask and dried in vacuo for ca. 30 min. The tripyrrane was dissolved in dry THF (600 mL) with triethylamine (10 drops) and 10% Pd on carbon (600 mg) and the reaction was stirred at room temperature under one atmosphere of H 2 . After 15 h, the suspension was filtered through celite to remove the catalyst and the resulting clear solution was concentrated under reduced pressure to yield a light pink solid. This material, obtained in near quantitative yield, was taken on to the next step without further purification. 2, 5-Bis[ (5-formyl-3- (3 -hydroxy propyl) -4- methylpyrrol-2-yl) methyl] -3, 4-diethylpyrrole l p , Fig. IB . 2,5-Bis[ (3-(3-(hydroxypropyl)-5-carboxyl-4- methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole 1 E (10 g, 0.02 mol) was placed in a 250 mL round bottom flask and dried in vacuo for ca. 1 h. At room temperature under nitrogen, trifluoroacetic acid (31 mL, 0.40 mol) was added dropwise via syringe. The tripyrrane dissolved with visible evolution of C0 2 to form a homogeneous yellow solution. The reaction was stirred at room temperature for ca. 15 min, then cooled to -20°C using a dry ice/CCl 4 bath. Freshly distilled triethylorthoformate (31 mL, 0.20 mol, dried over CaH ) was added via a syringe to produce a dark orange/yellow solution. This mixture was stirred an additional 10 min at -20°C, then the cold bath was removed and 100 mL of distilled water was added dropwise to the solution. The resulting brown suspension was stirred at room temperature for 15 min. The product was collected by filtration, washed several times with water and re- suspended into a 50 mL/100 mL/50 mL (H 2 0:Et0H:NH 4 0H, v/v) mixture. The yellow/brown suspension was stirred for 1 h, filtered, washed several times with water, and then rinsed with a small amount of cold 95% ethanol. At this point, TLC analysis showed a mixture of tripyrranes. Therefore, the crude dialdehyde tripyrrane and LiOH«H 2 0 (2.10 g, 0.05 mol) were added to 400 mL of degassed 95% MeOH and the suspension heated to reflux under a N 2 atmosphere. The reaction became homogeneous when heated and after ca. 1 h, it was slowly cooled to room temperature. The reaction mixture was concentrated under reduced pressure to 75 mL and the resulting slurry placed in the freezer for several hours. The product was filtered and then purified by forming a slurry with 400 mL of methanol and 50 mL of water and heating close to boiling. The suspension was slowly cooled to room temperature, reduced to 150 mL under reduced pressure, and placed in the freezer for several hours. The purified dialdehyde tripyrrane was filtered, rinsed with water and dried in vacuo for 24 h to yield 7.65 g (80%) of a light tan powder. For 1 F : mp 164-166°C; *H NMR (CD3OD) : δ 0.96 (t, 6H, CH 2 C# 3 ) , 1.49 (p, 4H, CH 2 C# 2 CH 2 OH) , 2.25 (s, 6H, pyrr-CH 3 ) , 2.32-2.43 (m, 8H, Cff 2 CH 3 and CJΪ 2 CH 2 CH 2 OH) , 3.46 (t, 4H, CH 2 CH 2 CH 2 OH) , 3.85 (s, 4H, (pyrr) 2 -CH 2 ) , 9 .34 (s , 2H, CHO) ; Cl MS , M + : m/e 480 ; HR MS , M + : m/e 481.2942 (calcd. for C 2 gH 39 3θ 4 , 481.2941) . 4 , 5-Diethyl-10 ,23 -dimethyls ,24-bis (3- hydroxy propyl) -16, 17 -bis (3 -hydroxy propyloxy) - 13 ,20,25,26, 27-pentaazapentacyclo [20.2.1.1 3 > 6 .1 8 > U . o 14 > 19 ] heptacosa-3 , 5 , 8, 10, 12, 14, 16, 18 ,20 ,22 ,24-undecaene (IJJ, Fig. IB) . 2 , 5-Bis [ (5-formyl-3- (3-hydroxypropyl) -4- methylpyrrol-2-yl) methyl] -3 , 4-diethylpyrrole lp (1.00 g, 0.002 mol) and l, 2-diamino-4 , 5-bis (3-hydroxy- propyloxy)benzene I Q (0.52 g, 0.002 mol) were placed in a 2 L round bottom flask with 1000 mL of toluene and 200 mL of methanol. The solvents were purged with nitrogen prior to use. Concentrated HCl (0.5 mL) was added and the reaction heated to reflux under nitrogen. The reaction went from a clear suspension of starting materials to a dark red homogeneous solution as the reaction proceeded. After 5 h the reaction was cooled to room temperature and the solvents removed under reduced pressure until the product precipitated out of solution. The remainder of the solvent was decanted off and the macrocycle dried in vacuo. The dark red product was recrystallized from methanol/diethylether and yielded 1.4-1.5g (90-100%). For 1 R : mp 190°C dec; *H NMR (CD3OD) : δ 1.11 (t, 6H, CH 2 Cff 3 ) , 1.76 (p, 4H, pyrr-CH 2 C# 2 CH 2 OH) , 2.03 (p, 4H, OCH 2 CH 2 CH 2 OH) , 2.36 (s, 6H, pyrr-CH 3 ) , 2.46 (q, 4H, Cff 2 CH 3 ) , 2.64 (t, 4H, pyrr-CH 2 CH 2 CH 2 OH) , 3.61 (t, 4H, pyrr-CH 2 CH 2 Cff 2 OH) , 3.77 (t, 4H, OCH 2 CH 2 CH 2 OH) , 4.10 (s, 4H, (pyrr) 2 -CH 2 ) , 4.22 (t, 4H, OC# 2 CH 2 CH 2 OH) , 7.41 (s, 2H, PhH) , 8.30 (S, 2H, HC=N) ; 13 C NMR (CD3OD) : δ 10.0, 17.2, 18.6, 20.9, 24.5, 33.2, 33.5, 59.6, 61.9, 67.8, 107.1, 120.7 123.8, 125.0, 125.8, 128.7, 144.8, 145.0, 150.7, 154.6; UV/vis (CH3OH) [λ-na j -, nm] 365; FAB MS, (M+H) + : m/e 703; HRMS, M + : m/e 701.4120 (calcd. for C^^N^: 701.4152). Anal, calcd. tC 4 oH 55 N 5 0 6 ] (HCl) (CH3OH) : C, 63 . 92 ; H, 7.85 ; N, 9. 09 ; Cl , 4 . 60. Found: C, 64 . 17 ; H, 7 . 68 ; N, 9. 39 ; Cl , 4 .70. General procedure for the synthesis of water soluble lanthanide (III) 4,5-diethyl-10,23-dimethyl-9,24-bis (3- hydroxy propyl) -16, 17- (3 -hydroxy propyloxy) -13,20,25,26,27- pentaazapentacyclo[20.2.1.1^'°. i°Η .0^'^] heptacosa- 1,3,5, 7, 9, 11 (27) , 12, 14, 16, 18,20,22 (25) ,23-tridecaene, B2T2TXP (l j , Fig. IC) . One equivalent of the hydrochloride salt of the macrocycle, 4,5-diethyl-10,23- dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis(3- hydroxypropyloxy)-13,20,25,26,27-pentaazapentacyclo [20.2.1.1 3 ' 6 .l 8 ' π .0 14 ' 19 ]heptacosa- 3,5,8,10,12,14,16,18,20,22,24-undecaene 1 H , 1.5 equivalents of the Ln(Nθ3)3«XH 2 0 metal salt, 2-3 equivalents of tetrabutylammonium nitrate (TBANO3) and triethylamine (ca. 1 mL) were mixed together in methanol and heated to reflux under air. After completion of the reaction (as judged by the UV/vis spectrum of the reaction mixture) , the deep green solution was cooled to room temperature, the solvent removed under reduced pressure and the crude complex dried in vacuo for several hours. A solution of dichloromethane/methanol (99:1 v/v) was added to the crude complex and the suspension was sonicated a few min. The green suspension was filtered in order to remove red/brown colored impurities in the filtrate (incomplete oxidation products and excess triethylamine) . The resulting deep green solid was first dissolved in methanol and then chloroform was added to reduce the polarity of the mixture (1:2 v/v). This solution was filtered through celite and loaded on a (pre-treated/pre-washed 1M NaNθ3) neutral alumina column (10 cm). The column was first eluted with a 1:10 (v/v) methanol/chloroform solution by gravity to remove a reddish brown impurity. The metal complex was then obtained by eluting the column with chloroform containing increasing amounts of methanol (20-50%) . The purified lanthanide (III) texaphyrin complex was recrystallized by dissolving the complex in methanol/chloroform and carefully layering the dark green solution with a small amount of methanol, then with diethy1ether. The layered solution was kept at room temperature in the dark for a few days. Some of the lanthanide (III) texaphyrin complexes formed single crystals by this method. Other complexes were recrystallized twice for analytically pure measurements and characterizations. Lanthanum (III) complex, l j . The hydrochloride salt of macrocycle l jj (300 mg, 0.407 mmol), La(N03)3«6H 2 0 (350 mg, 0.814 mmol), TBANO3 (305 mg, 1.0 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 10 h. After workup using the general procedure outlined above, 132 mg of the complex was obtained (34%). For l j : *H NMR (CD3OD) : δ 1.68 (t, 6H, CH 2 CH 3 ) , 2.22-2.30 (m, 4H, pyrr-CH 2 Ctf 2 CH 2 OH and 4H, OCH 2 Cff 2 CH 2 OH) , 3.20 (s, 6H, pyrr-CH 3 ) , 3.72-3.78 (m, 4H, CH 2 CH 3 and 4H, pyrr-CH 2 CH 2 CH 2 OH and 4H, pyrr-CH 2 CH 2 Cff 2 OH) , 3.94 (t, 4H, OCH 2 CH 2 CH 2 OH) , 4.78 (m, 4H, OCf 2 CH 2 CH 2 OH) , 9.37 (s, 2H, ArH) , 9.87 (s, 2H, (pyrr) 2 C=CH) , 11.71 (s, 2H, HC=N) ; 13 C NMR (CD3OD) : δ 11.0, 18.9, 20.3, 23.0, 33.3, 36.3, 59.7, 62.2, 68.1, 101.5, 118.5, 137.1, 140.3, 144.6, 147.5, 148.2, 152.9, 154.9, 159.4; UV/vis: [ (MeOH) λ-uax, nm (log e)]: 355 (4.34), 417 (4.73), 476 (5.06), 685.5 (4.08), 746 (4.59); FAB MS, M + : m/e 835; HRMS, (M+H) + : m/e 836.2919 (calcd. for 836.2903). Anal, calcd. for [C 40 H 50 N 5 O 6 La] (N0 3 ) 2 (H 2 0) 2 : C, 48.23; H, 5.47; N, 9.85. Found: C, 47.93; H, 5.41; N, 9.77. Cerium (III) complex 1 . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Ce(N0 3 )3«6H 2 0 (265 mg, 0.611 mmol), TBANO3 (305 mg, 1.0 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 7 h. It is important to note that initially the reaction mixture formed a suspension, however, as the product formed the solution became homogeneous. After workup using the general procedure outlined above, 143 mg of dark green crystals were obtained (37%) . This material was suitable for X-ray diffraction analysis. For 1^: UV/vis: [ (MeOH) λ jj ^, nm (log e)]: 349.5 (4.34), 416.5 (4.70) 476.5 (5.05), 684 (4.07), 741 (4.56); FAB MS, M + : m/e 836; HRMS, (M+H) + : m/e 836.2807 (calcd. for C 4 oH 51 N 5 0 6 140 Ce, 836.2816). Anal, calcd. for [C 40 H 50 N 5 O 6 Ce] (N0 3 ) 2 (H 2 0) 3 : C, 47.32; H, 5.56; N, 9.66. Found: C, 46.98; H, 5.22; N, 9.63. Praseodymium (III) complex 1 L . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Pr(N0 3 )3*5H 2 0 (255 mg, 0.611 mmol), TBANO3 (305 g, 1.0 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 10 h. After workup using the general procedure outlined above, 200 mg of the complex was obtained (51%). For 1 L : UV/vis: [(MeOH) X^^, nm (log e)]: 352 (4.32), 416.5 (4.69), 476.5 (5.04), 689 (4.07), 744.5 (4.57); FAB MS, M + : m/e 838; HRMS, M + : m/e 837.2823 (calcd. for C 40 H 50 N 5 O 6 141 Pr, 837.2838). Anal, calcd. for (N0 3 ) 2 (CH 3 OH) (H 2 0) : C, 48.65; H, 5.58; N, 9.69. Found: C, 48.75; H, 5.52; N, 9.71. Neodymium (III) complex 1 M . The hydrochloride salt macrocycle 1 H (300 mg, 0.407 mmol), Nd(N0 3 )3«6H 2 0(267 mg, 0.611 mmol), TBANO3 (305 mg, 1.0 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 12 h. After workup using the general procedure outlined above, 125 mg of the complex was obtained (32%). For 1 M : UV/vis: [(MeOH) λ,^, nm (log e)]: 353.5 (4.32), 416 (4.68), 476 (5.05), 688 (4.06), 742.5 (4.56); FAB MS, M + : m/e 839; HRMS, M + : m/e 838.2828 (calcd. for C 4 oH 5 oN 5 0 6 142 Nd, 838.2838). Anal, calcd. for (N0 3 ) 2 (CH 3 0H) : C, 49 .48 ; H, 5.47 ; N, 9.86. Found: C, 49.23 ; H, 5. 49 ; N, 9 .83 . Samarium (III) complex 1 N . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Sm(N03)3«5H 2 0 (270 mg, 0.611 mmol), TBANO3 (305 mg, 1.0 mmol) and triethylamine (ca. 0.5 mL) in 350 ml methanol were heated to reflux under air for 7 h. After workup using the general procedure outlined above, 183 mg of a dark green crystalline solid was obtained (46%) . This material has the potential for X-ray diffraction. For 1^: UV/vis: [(MeOH) λπ j ax, nm (log e)]: 354.5 (4.36), 415.5 (4.71), 475.5 (5.09), 682 (4.09), 741 (4.61); FAB MS, M + : m/e 849; HRMS, M + : m/e 848.2957 (calcd. for CoH 5 oN 5 0 6 152 Sm, 848.2959). Anal, calcd. for (N0 3 ) 2 (CH 3 OH) : C, 48.99; H, 5.42; N, 9.76. Found: C, 48.79; H, 5.64; N, 9.43. Europium (III) complex IQ . The hydrochloride salt of macrocycle l jj (400 mg, 0.543 mmol), Eu(Nθ3) 3 «5H 2 0 (290 mg, 0.65 mmol), TBANO3 (500 mg, 1.64 mmol) and triethylamine (ca 1 mL) in 350 mL methanol were heated to reflux under air for 16 h. After workup using the general procedure outlined above, 255 mg of a dark green crystalline solid was obtained (48%) . This material was suitable for X-ray diffraction analysis. For I Q : UV/vis: [(MeOH) λ maχf nm (log e)]: 414 (4.72), 475.5 (5.10), 678 (4.08), 739.5 (4.63); FAB MS, (M+H) + : m/e 850; HRMS, M + : m/e 849.2961 (calcd. for C 0 H 5 oN 5 0 6 153 Eu, 849.2974). Anal, calcd. for [C 40 H 5 oN 5 0 6 Eu] (N0 3 ) 2 (H 2 0): C, 47.56; H, 5.39; N, 9.71. Found: C, 47.47; H, 5.45; N, 9.64. Gadolinium (III) complex l p . The hydrochloride salt of macrocycle 1 H (750 mg, 1 mmol), Gd(N03)3*5H 2 0 (660 mg, 1.5 mmol), TBANO3 (930 mg 3.0 mmol) and triethylamine (ca. l mL) in 600 mL methanol were heated to reflux under air for 12 h. After workup using the procedure outlined above, the dark green complex was recrystallized from chloroform/methanol/diethylether to yield 700 mg (72%) of a deep green crystalline solid. X-ray quality single crystals were obtained by dissolving the complex in methanol/chloroform and carefully layering the dark green solution with a small amount of methanol, then with diethylether. The layered solution was kept at room temperature in the dark for a few days. For lp: UV/vis: [(MeOH) λ jj ^, nm (log e)]: 358 (4.33), 416 (4.72), 478 (5.12), 678 (4.03), 737.5 (4.64); [ (H 2 0) λ-^, nm (log e)]: 347 (4.43), 419 (4.75), 469 (5.08), 740 (4.60). IR (KBr, cm -1 , major peaks): υ 3299 (OH), 1647 (C=N) , 1601 (C=N) , 1507, 1456, 1437, 1385 (NO3-) , 1290, 1221, 1098, 1082. FAB MS, M + : m/e 854; HRMS, M + : m/e 854.2989 (calcd. for C 4Q H 5() N5θ 6 1 ' 8 Gd, 854.300. Anal, calcd. for (N0 3 ) 2 (CH 3 OH) (H 2 0): C, 47.85; H, 5.49; N, 9.53. Found: C, 47.62; H, 5.37; N, 9.54. NOTE: If the alumina is not pre-treated with a NaNθ wash, the Gd(III) will not have two nitrate counter anions, instead it will have one nitrate and one chloride counter anion: Anal, calcd. for [C 40 H 50 N 5 O 6 Gd] (N0 3 )C1(H 2 0) 2 : C, 48.65; H, 5.51; N, 8.51; Cl, 3.59. Found: C, 48.21; H, 5.58; N, 8.34; Cl, 3.62. Terbium (III) complex IQ . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Tb(N03)3«6H 2 0 (276 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 12 h. After workup using the general procedure outlined above, 152 mg of the complex was obtained (38%). For IQ: UV/vis: [(MeOH) λ mSiχf nm (log e)]: 353 (4.35), 414 (4.71), 474.5 (5.09), 680 (4.08), 737 (4.62); FAB MS, M + : m/e 856; HRMS, M + : m/e 855.3017 (calcd. for C 0 H5øN 5 O 6 159 Tb, 855.3015). Anal, calcd. for [C^^ j OgTb] (N0 3 ) 2 (CH 3 OH) (H 2 0) : C, 47.80; H, 5.48; N, 9.52. Found: C, 48.11; H, 5.28; N, 9.75. Dysprosium (III) complex 1 R . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Dy(Nθ3) «5H 2 0 (266 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 5 h. After workup using the general procedure outlined above, 250 mg of the complex was obtained (62%). For 1 R : UV/vis: [(MeOH) X^- j , nm (log e)]: 354 (4.32), 414 (4.68), 475 (5.07), 677.5 (4.03), 735.5 (4.60); FAB MS, (M+H) + : m/e 861; HRMS, M + : m/e 860.3048 (calcd. for 860.3053). Anal, calcd. for (N0 3 ) 2 (H 2 0) : C, 47.89; H, 5.23; N, 9.78. Found: C, 47.97; H, 5.22; N, 9.72. Holmiu (III) complex 1 § . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Ho(N03)3«5H 2 0 (269 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 12 h. After workup using the general procedure outlined above, 220 mg of the complex was obtained (55%). For l s : UV/vis: [(MeOH) λ j ^^, nm (log e)]: 354 (4.35), 414 (4.72), 475.5 (5.12), 677 (4.08), 734 (4.65); FAB MS, M + : m/e 862; HRMS, M + : m/e 861.3044 (calcd. for CoH 50 N5θ 6 165 Ho, 861.3064). Anal, calcd. for [C 40 H 50 N 5 O 6 Ho] (N0 3 ) 2 (CH 3 OH) (H 2 0) : C, 47.52; H, 5.45; N. 9.47. Found: C, 47.55; H, 5.26; N, 9.30. Erbium (III) complex l j . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Er(N0 3 ) 3 «5H 2 0 (270 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 12 h. After workup using the general procedure outlined above, 143 mg of the complex was obtained (36%). For l τ : UV/vis: [(MeOH) λ jj ^, nm (log e)]: 355.5 (4.36), 414.5 (4.72), 477 (5.13), 672 (4.08), 732 (4.66); FAB MS, M + : m/e 863; HRMS, M + : m/e 865.3110 (calcd. for CoH 5 oN 5 0 6 166 Er, 862.3064). Anal, calcd. for [C 40 H 50 N 5 O 6 Er] (N0 3 ) 2 (CH 3 0H) : C, 48.32; H, 5.34; N, 9.63. Found: C, 48.14; H, 5.14; N, 9.55. Thulium (III) complex ly. The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Tm(N0 3 )3 ' 5H 2 0 (274 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 22 h. After workup using the general procedure outlined above, 150 mg of the complex was obtained (37%) . This complex is more difficult to purify due to its lower solubility in methanol/chloroform solutions, which leads to its lower yield. For l^ j - UV/vis: [(MeOH) X,^, nm (log e)]: 355.5 (4.36), 414.5 (4.72), 477 (5.13), 672 (4.08), 732 (4.66); FAB MS, M + : m/e 866; HRMS, M + : m/e 865.3110 (calcd. for C 40 H 50 N 5 O 6 169 Tm, 865.3103). Anal, calcd. for [C 40 H 50 N 5 O 6 Tm] (N0 3 ) 2 (H 2 0) 2 : C, 46.82; H, 5.31; N, 9.56. Found: C, 46.85; H, 5.23; N, 9.38. Ytterbium ( III) complex ly. The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Yb(N03) 3 «5H 2 0 (274 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 24 h. After workup using the general procedure outlined above, 220 mg of the complex was obtained (54%). For l y : FAB MS, M + : m/e 870; HRMS, M + : m/e 870.3132 (calcd. for 870.3149). Lutetium (III) complex l w . The hydrochloride salt of macrocycle 1 H (300 mg, 0.407 mmol), Lu(N03) 3 »H 2 0 (220 mg, 0.611 mmol), TBANO3 (305 mg, 1.64 mmol) and triethylamine (ca. 0.5 mL) in 350 mL methanol were heated to reflux under air for 24 h. After workup using the general procedure outlined above, 150 mg of the complex was obtained (37%) . This complex has very low solubility in methanol/chloroform solution. Almost half of the product remained on the column during purification. For l w : FAB MS, M + : m/e 872; HRMS, M + : m/e 871.3154 (calcd. for C 40 H 5 oN 5 0 6 175 Lu, 871.3169). Acid-catalyzed Schiff-base condensation between IQ and l produced the so-called "sp 3 " nonaromatic macrocycle l j in quantitative yield. Macrocycle l jj is quite stable, decomposing only slightly over a period of months when stored in freezer. Oxidation and metallation of lg in the presence of 1.5 equivalents of lanthanide(III) metal salt, triethylamine, and air in boiling methanol produces a deep green metal complex within 3-24 hours (as judged by UV-Vis) of reaction time. All the lanthanide(III) [La-Lu, except Pm] texaphyrin complexes l j -lw were isolated with unoptimized yields ranging from 34%-75%. Satisfactory spectroscopic and mass spectrometric data were obtained for all new compounds. Single crystals suitable for X-ray diffraction analysis of the Eu(III) and Gd(III) complexes IQ and lp, respectively, were obtained by dissolving each complex in MeOH/CHCl3 and layering with diethyl ether. EXAMPLE 2 Synthesis of Europiu (III) T2B1 TXP-oligo conjugate. The present example provides for the synthesis of a texaphyrin metal complex-oligonucleotide conjugate useful for site-directed hydrolysis of ester bonds of a complementary nucleic acid (see Figures 2A and 2B) . 4- Amino- 1- 11- (ethyloxy) cetyl-2-oxy] -3 -nitrobenzene 2 jj , n=l . Potassium carbonate (14.0 g, 101 mmol) and 4- amino-3-nitrophenol 2^ (10.0 g, 64.9 mmol) were suspended in 150 mL dry acetonitrile. Ethyl-2-iodoacetate (10 mL, 84.5 mmol) (or ethyl iodobutyrate may be used, in that case n=3) was added via syringe, and the suspension was stirred at ambient temperature for ca. 21 h. Chloroform (ca. 375 mL) was added, and used to transfer the suspension to a separatory funnel, whereupon it was washed with water (2 x ca. 100 mL) . The water washes were in turn washed with CHC1 3 (ca. 100 mL) and the combined CHCI3 extracts were washed with water (ca. 100 mL) . Solvents were removed on a rotary evaporator, and the residue was redissolved in CHCI3 (ca. 500 mL) and precipitated into hexanes (1.5 L) . After standing two days, the precipitate was filtered using a coarse fritted funnel and dried in vacuo to provide 14.67 g compound 2JJ, n=l (94.1%). TLC: Rf = 0.43, CHCI3. 4 -Amino- 1 -[1- (hydroxy) acetyl -2 -oxy] -3 -ni trobenzene 2 Q , n=l . 4-Amino-l-[l-(ethyloxy)acetyl-2-oxy]-3- nitrobenzene 2g, n=l, (10.00 g, 37.3 mmol) was dissolved in tetrahydrofuran (100 mL) , aqueous sodium hydroxide (1M solution, 50 mL) was added and the solution was stirred at ambient temperature for ca. 21 h. Tetrahydrofuran was removed on a rotary evaporator, and water (100 mL) was added. The solution was washed with CHCI3 (ca. 200 mL) , then neutralized by addition of hydrochloric acid (1M solution, 50 mL) . The precipitate which formed was filtered after standing a few minutes, washed with water, and dried in vacuo to provide 8.913 g compound 2 Q , n=l (99.5%). TLC: Rf = 0.65, 10% methanol/CHCL j . 16- [1- (Hydrooxy) acetyl-2-oxy]-9 , 24-bis (3- hydroxy propyl) -4 , 5-diethyl-10 , 23 -dimethyl- 13 , 20 , 25 , 26 ,27- pentaazapenta-cyclo [20.2.1.1 3,6 .1°Η.0 14,19 ] heptacosa- 3, 5, 8, 10, 12, 14 (19) , 15, 17,20,22 ,24-undecaene 2 E , n=l . 4- Amino-l-[l-(hydroxy)acetyl-2-oxy]-3-nitrobenzene 2 C , n=l (1.800 g, 8.49 mmol) was dissolved in methanol (100 mL) in a 1 L flask. Palladium on carbon (10%, 180 mg) was added, and the atmosphere inside the flask was replaced with hydrogen at ambient pressure. A grey precipitate was formed after ca. 3 h, and the supernatant was clear. Methanol was removed in vacuo, taking precautions to prevent exposure to oxygen, and the compound was dried overnight in vacuo. Isopropyl alcohol (500 mL) and HCl (12 M, 400 μL) were added, and the suspension was allowed to stir for ca. 15'. 2,5-Bis[(3-hydroxypropyl-5-formyl- 4-methylpyrrol-2-yl)methyl ]-3,4-diethylpyrrole 2 D (n=l) (4.084 g, 8.49 mmol) was added, and the reaction stirred at room temperature under argon for 3 hours. Hydrochloric acid was again added (12 M, 400 μL) and the reaction again was allowed to stir for an additional 3.5 h. The resulting red solution was filtered through celite, and the filtercake was washed with isopropyl alcohol until the filtrate was colorless. Solvent was reduced to a volume of ca. 50 mL using a rotary evaporator, whereupon the solution was precipitated into rapidly stirring Et 2 0 (ca. 700 mL) . Compound 2 E (n=l) was obtained as a red solid (5.550 g, 98.4%) upon filtering and drying in vacuo. TLC: Rf = 0.69, 20% methanol/CHCI3 (streaks, turns green on plate with I 2 ) . Europium (III) complex of 16- [1- (hydroxy) acet '1-2- oxy]-9 ,24-bis (3 -hydroxy propyl) -4,5-d iethyl-10 ,23- dimethyl-13 ,20 ,25,26, 27 -pentaazapentacyclo [20.2. l .l 3 ' 6 .1 8 ' 11 .0 14 ' 19 ]heptacosa-l, 3, 5, 7, 9, 11 (27) , 12, 14 (1 9) , 15, 17 ,20,22 (25) ,23-tridecaene 2 p , n=l . The protonated form of the macrocycle, 16-[1-(hydroxy)acety1-2-oxy]- 9,24-bis(3-hydroxypropyl)-4,5-d iethyl-10,23-dimethyl- I3,20,25,26,27-pentaazapentacyclo[20.2 .l.l 3 ' 6 .! 8 ' 11 ^ 14 ' 19 ] heptacosa-3,5,8,10,12,14(19) ,15,17,20,22,24-undecaene hydrochloride 2 E , n=l (500 mg, 753 μmol) , europium(III) acetate pentahydrate (334 mg, 797 μmol) and triethylamine (1.33 mL, 8.0 mmol) in 150 mL of methanol were heated to reflux under air for 5.5 h. The reaction was cooled to room temperature, and stored at -20 °C overnight. Solvent was removed on a rotary evaporator, acetone (200 mL) was added, and the suspension was stirred on a rotary evaporator for 2 h. The suspension was filtered and the precipitate was dried briefly in vacuo, whereupon a solution was formed in methanol (ca. 250 mL) and water (25 mL) . The pH was adjusted to 4.0 using HCl (1 M) , HCl-washed zeolite LZY54 was added (ca. 5 g) and the suspension was stirred on the rotary evaporator for ca. 6 h. Amberlite™ IRA-900 ion exchange resin (NaF treated, ca. 5 g) was added, and the suspension was stirred for an additional hour. The suspension was filtered, the resin was washed with methanol (ca. 100 mL) , and the filtrate was adjusted to pH 4.0 using HCl (1 M) . Solvents were removed on a rotary evaporator, using ethanol (abs.) to remove traces of water. After drying in vacuo, the compound was dissolved in methanol (25 mL) and precipitated into rapidly stirring Et 2 0 (300 mL) . Compound 2p, n=l was obtained as a olive precipitate (303 mg, 48.4%) after filtering and drying in vacuo. An analytical sample was prepared by treating 50 mg of 2 F , n=l dissolved in methanol (25 mL) with acetic acid-washed zeolite, then acetic acid-washed Amberlite™ for ca. 1 h. After reducing methanol to a minimum volume, the solution was precipitated into rapidly stirring Et 2 0 (70 mL) , filtered, and dried in vacuo. Analysis. Calculated for (C 36 H39N 5 0 5 Eu) (CH 3 C0 2 ) (H 2 0) : C, 53.66; H, 5.21, N, 8.23. Found: C, 53.39, H, 5.50, N, 8.25. HR FAB mass spectrum, M + : Calculated for C 36 H 4 N 5 05EU, 773.2228. Found: 773.2239. UV/vis (MeOH) [λrøax, nm (log e) ] : 330.0 (4.47), 464.0 (4.72), 708.0 (3.90), 762.0 (4.35). Postsynthetic modification of oligodeoxynucleotide- amine 2 Q (9 E ) with europium (III) complex 2 p , n=l . The europium(III) complex of 16-[1-(hydroxy)acety1-2-oxy]- 9,24-bis(3-hydroxypropyl)-4,5-d iethyl-10,23-dimethyl- 13,20,25,26,27-pentaazapentacyclo [20.2.1.1 3 ' 6 .l 8 ' π .0 14 ' 19 ]heptacosa-l,3,5,7,9,ll(27) ,12, 14(19) ,15,17,20,22(25) ,23-tridecaene 2p, n=l, (25 mg, 30.1 μmol) and N-hydroxysuccinimide (5 mg, 43 μmol) were dried together overnight in vacuo. The compounds were dissolved in dimethylformamide (anhydrous, 500 μL) and dicyclohexyl-carbodiimide (10 mg, 48 μmol) was added. The resulting solution was stirred under argon with protection from light for 8h, whereupon a 110 μL aliquot was added to a solution of oligodeoxynucleotide 2Q (87 nmol) in a volume of 350 μL of 0.4 M sodium bicarbonate buffer in a 1.6 mL eppendorf tube. After vortexing briefly, the solution was allowed to stand for 23 h with light protection. The suspension which formed was filtered through 0.45 μm nylon microfilterfuge tubes, and the eppendorf tube was washed with 250 μL sterile water. The combined filtrates were divided into two eppendorf tubes, and glycogen (20 mg/mL, 2 μL) and sodium acetate (3M, pH 5.4, 30 μL) were added to each tube. After vortexing, ethanol (absolute, 1 mL) was added to each tube to precipitate the DNA. Ethanol was decanted following centrifugation, and the DNA was washed with an additional 1 mL aliquot of ethanol and allowed to air dry. The pellet was dissolved in 50% formamide gel loading buffer (20 μL) , denatured at 90 °C for ca. 2 ' , and loaded on a 20% denaturing polyacrylamide gel. The yellow band corresponding to conjugate 2 H , n=l (9 D , 10 A ) was cut from the gel, crushed, and soaked in IX TBE buffer (ca. 7 mL) for 1-2 days. The suspension was filtered through nylon filters (0.45 μm) and desalted using a Sep-pak™ reverse phase cartridge. The conjugate was eluted from the cartridge using 40% acetonitrile, lyophilized overnight, and dissolved in ImM HEPES buffer, pH 7.0 (500 μL) . The solution concentration determined using UV/vis spectroscopy (calculated e 2 ^= 187,110) was 21.6 μM in conjugate 2 H , n=l (9 D , 10 A ) (12%) . EXAMPLE 3 Synthesis of texaphyrin metal complexes with amine, thiol or hydroxy linked oligonucleotides, see Fig. 3A-3C. Amides, ethers and thioethers are representative of linkages which may be used for coupling site-directed molecules such as oligonucleotides to texaphyrin metal complexes (see Figures 3A-3C) . Oligonucleotides or other site-directed molecules functionalized with amines at the 5'-end, the 3'-end, or internally at sugar or base residues are modified post-synthetically with an activated carboxylic ester derivative of the texaphyrin complex. Alternatively, oligonucleotide analogues containing one or more thiophosphate or thiol groups are selectively alkylated at the sulfur atom(s) with an alkyl halide derivative of the texaphyrin complex. Oligodeoxynucleotide-complex conjugates are designed so as to provide optimal catalytic interaction between the targeted RNA phosphoester backbone and the texaphyrin- bound lanthanide cation(s) . Oligonucleotides are used to bind selectively compounds which include the complementary nucleotide or oligo- or poly-nucleotides containing substantially complementary sequences. As used herein, a substantially complementary sequence is one in which the nucleotides generally base pair with the complementary nucleotide and in which there are very few base pair mismatches. Oligonucleotides are used, for example, as hybridization probes in blot analyses, primers for polymerase chain reaction (PCR) amplification, and for site-specific mutagenesis. Oligonucleotide-derived products are being used for the detection of genetic diseases and for proviral HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS) . They are also being considered as potential chemotherapeutic agents, for example, in gene therapy, and in an antisense capacity. The oligonucleotide may be large enough to bind probably at least 9 nucleotides of complementary nucleic acid. A general method for preparing oligonucleotides of various lengths and sequences is described by Caracciolo et al . (1989) Science , 245:1107. In general, there are two commonly used solid phase- based approaches to the synthesis of oligonucleotides containing conventional 5'-3' linkages, one involving intermediate phosphoramidites and the other involving intermediate phosphonate linkages. In the phosphoramidite synthesis a suitably protected nucleotide having a cyanoethylphosphoramidate at the position to coupled is reacted with the free hydroxyl of a growing nucleotide chain derivatized to a solid support. The reaction yields a cyanoethylphosphite, which linkage must be oxidized to the cyanoethylphosphate at each intermediate step, since the reduced form is unstable to acid. The phosphonate based synthesis is conducted by the reaction of a suitably protected nucleotide containing a phosphonate moiety at a position to be coupled with a solid phase-derivatized nucleotide chain having a free hydroxyl group, in the presence of a suitable activator to obtain a phosphonate ester linkage, which is stable to acid. Thus, the oxidation to the phosphate or thiophosphate can be conducted at any point during synthesis of the oligonucleotide or after synthesis of the oligonucleotide is complete. The phosphonates can also be converted to phosphoramidate derivatives by reaction with a primary or secondary amine in the presence of carbon tetrachloride. To indicate the two approaches generically, the incoming nucleotide is regarded as having an "activated" phosphite/phosphate group. In addition to employing commonly used solid phase synthesis techniques, oligonucleotides may also be synthesized using solution phase methods such as triester synthesis. The methods are workable, but in general, less efficient for oligonucleotides of any substantial length. Preferred oligonucleotides resistant to in vivo hydrolysis may contain a phosphorothioate substitution at each base (J. Org. Chem. , 55:4693-4699, (1990) and Agrawal, (1990)). Oligodeoxy- nucleotides or their phosphorothioate analogues may be synthesized using an Applied Biosystem 38OB DNA synthesizer (Applied Biosystems, Inc., Foster City, CA) . EXAMPLE 4 Synthesis of diformyl monoacid tripyrrane H and oligonucleotide conjugate j , see Fig. 4A-4D. Dimethylester Dibenzylester Dipyrromethane 4 β : A three-neck 1000 ml round-bottom flask set with a magnetic stirring bar, a thermometer, a heating mantle, and a reflux condenser attached to an argon line was charged with methylester acetoxypyrrole 4 A (100.00 g; 267.8 mmol) , 200 proof ethyl alcohol (580 ml) , and deionized water (30 ml.) The reaction mixture was heated up and when the resulting solution began to reflux, 12 N aq. hydrochloric acid (22 ml) was added all at once. The flask contents were stirred under reflux for two hours. The heating element was replaced by a 0 °C bath and the resulting thick mixture was stirred for two hours prior to placing it in the freezer overnight. The mixture was filtered over medium fritted glass funnel, pressed with a rubber dam, and washed with hexanes until the filtrate came out colorless. The collected solids were set for overnight high vacuum drying at 30 'C to afford slightly yellowish solids (65.85 g, 214.3 mmol, 80.0 % yield.) Dimethylester Diacid Dipyrromethane, Q All the glassware was oven dried. A three-neck 2000 ml round- bottom flask set with a magnetic stirring bar, a hydrogen line, and a vacuum line was charged with dimethylester dibenzylester dipyrromethane β (33.07 g, 53.80 mmol), anhydrous tetrahydrofuran (1500 ml) , and 10 % palladium on charcoal (3.15 g.) The flask was filled with dry hydrogen gas after each of several purges of the flask atmosphere prior to stirring the reaction suspension under a hydrogen atmosphere for 24 hours. The solvent of the reaction suspension was removed under reduced pressure. The resulting solids were dried under high vacuum overnight. The dry solids were suspended in a mixture of saturated aqueous sodium bicarbonate (1500 ml) and ethyl alcohol (200 ml) , and stirred at its boiling point for five minutes. The hot suspension was filtered over celite. The filtrate was cooled down to room temperature and acidified to pH 6 with 12 N aqueous hydrochloric acid. The resulting mixture was filtered over medium fritted glass. The collected solids were dried under high vacuum to constant weight (21.63 g, 49.78 mmol, 92.5 % yield.) Methyleεter Dibenzylester Tripyrrane, 4 E A three- neck 2000 ml round-bottom flask set with a heating mantle, a magnetic stirring bar, a thermometer, and a reflux condenser attached to an argon line was charged with dimethylester diacid dipyrromethane A Q (21.00 g, 48.33 mmol), ethyl acetoxy pyrrole D (30.50 g) , p- toluenesulfonic acid monohydrate (1.94 g) , trifluoroacetic acid (39 ml) , and methyl alcohol (1350 ml.) The flask contents were heated and stirred under reflux for two hours. The heating element was replaced with a 0 β C and the stirring was continued for half an hour prior to placing the resulting mixture in a freezer overnight. The cold mixture was filtered over medium fritted glass. The collected solids were washed with hexanes and dried under high vacuum overnight (13.05 g, 19.25 mmol, 39.8 % yield.) Methylester Diacid Tripyrrane F : All the glassware was oven dried. A three-neck 500 ml round-bottom flask set with a magnetic stirring bar, a hydrogen line, and a vacuum line was charged with methylester dibenzylester tripyrrane 4 E (12.97 g, 19.13 mmol), anhydrous tetrahydrofuran (365 ml) , and 10 % palladium on charcoal (1.13 g.) The flask was filled with dry hydrogen gas after each of several purges of the flask atmosphere prior to stirring the reaction suspension for 24 hours under a hydrogen atmosphere at room temperature. The reaction suspension was filtered over celite. The solvent of the filtrate was removed under reduced pressure to obtain a foam which was dried under high vacuum overnight (10.94 g, 21.99 mmol, 87.0 % pure.) Monoacid Tripyrrane R : All the glassware was oven dried. A three-neck 500 ml round-bottom flask set with a mechanical stirrer, a thermometer, a 0 °C bath, and an addition funnel set with an argon line was charged with methylester diacid tripyrrane F (10.20 g, 17.83 mmol). Trifluoroacetic acid (32.5 ml) was dripped into the reaction flask from the addition funnel over a 45 minute period keeping the flask contents below 5 °C. The resulting reaction solution was stirred at 0 °C for 15 minutes, and then at 20 'C for three hours. Triethylorthoformate (32.5 ml) was dripped into the flask from the addition funnel over a 20 minute period keeping the flask contents below -25 β C by means of a dry ice/ethylene glycol bath. The reaction solution was stirred for one hour at -25 * C and then a 0 °C bath was set up. Deionized water (32.5 ml) was dripped into the reaction flask from the addition funnel keeping the flask contents below 10 * C. The resulting two phase mixture was stirred at room temperature for 75 minutes and then added 1-butanol (200 ml.) The solvents were removed under reduced pressure. The resulting dark oil was dried under high vacuum overnight to obtain black solids (11.64 g.) A three-neck 2000 ml round-bottom flask set with a thermometer, a heating mantle, a magnetic stirring bar, and a reflux condenser attached to an argon line, was charged with the crude methylester diformyl tripyrrane 4 Q (11.64 g) , methyl alcohol (900 ml), deionized water (60 ml), and lithium hydroxide monohydrate (4.7 g.) The flask contents were heated, stirred under reflux for two hours, cooled down to room temperature, added deionized water (250 ml), acidified with 12 N aq. HCl to pH 5, and then stirred at 0 "C for one hour. The resulting mixture was filtered over medium fritted glass funnel. The collected solids were dried under high vacuum to constant weight prior to their purification by column chromatography (silica gel, MeOH in CH 2 C1 2 , 0-10 %; 3.64 g, 8.06 mmol, 45.2 % yield.) The monoacid tripyrrane 4g is condensed with a derivatized ortho-phenylene diamine, for example, I to form a nonaromatic precursor which is then oxidized to an aromatic metal complex, for example, 4 j . An oligonucleotide amine may be reacted with the carboxylic acid derivatized texaphyrin j to form the conjugate 4» having the site-directed molecule on the T portion of the molecule rather than the B portion. EXAMPLE 5 Hydrolysis of Monoesters by Lanthanide (III) T2B2 Texaphyrin The present example provides the utility of the present invention in the use of texaphyrin metal complexes for the hydrolysis of monoesters, in particular, the hydrolysis of UpU, cUMP, 3'-UMP and 2'-UMP. Cytosine, uridine, uridine-2' and 3'-monophosphate disodium salt (2'-UMP and 3'-UMP), uridine-2',3'- cyclicmonophosphate sodium salt (cUMP) , and uridylyl(3'→5') uridine ammonium salt (UpU) were purchased from Sigma (St. Louis, MO) and used without further purification. The lanthanide texaphyrins were prepared as in the previous examples. All solutions, unless otherwise stated, were prepared from a stock solution of 5.0 mM N-(2-hydroxyethyl) piperazine-N'- ethanesulfonic acid (HEPES) , in Milli-Q purified water, adjusted to pH 7.0. Solutions were stored and reactions conducted in RNAse free plastic vials further sterilized by heating at 120°C for 20 minutes in an autoclave. Gloves were worn at all times during solution preparation and reaction sampling. All kinetic runs were thermostated at 37°C in a water bath. High-performance liquid chromatography (HPLC) was performed on a Waters 501 equipped with a Waters model 440 absorbance detector, monitoring at 254 nm. A YMC, Inc., USA ODS-AQ column (150 mm x 4.6 mm I.D.) was used. Satisfactory separation was achieved with an isocratic gradient (10 mM NaH 2 P0 adjusted to pH 5.6 with 1% methanol) with a flow rate of 1.0 ml/min. A Beckman DU-7 spectrometer was used to confirm the concentrations of EuB2T2 txp. Eu(110 ) . In the control experiment, the reaction solutions were prepared by diluting 100 μl of UpU (2.94 mM) , 25 μl of Eu(N0 3 )3 (3.5 μm) , and 100 μl of cytosine (0.423 mM) , as internal standard, in 375 μl of 5.0 mM HEPES solution. The reactions were carried out as for EuB2T2 txp. The pseudo-zero order rate constant for the control reaction was determined to be = (2.2 ± 0.8) x 10 ^ * mM/h. EuB2T2 txp. In a typical kinetics experiment, the reaction solutions were prepared by diluting 100 μl of UpU (2.94 mM) , 50 μl Of EuB2T2 txp (7.8 mM) , and 100 μl of cytosine (0.423 mM) , as internal standard, in 350 μl of 5.0 mM HEPES solution. The rate of UpU hydrolysis was monitored by removing 15 μl aliquots which were frozen until HPLC analysis was possible. All samples were microfiltered (0.2 μm) prior to injection on the HPLC. All runs were performed in triplicate. The background as determined from the simultaneous control containing no metal complex was negligible. The pseudo-zero order rate constant for the reaction was determined to be k = (9.1 ± 1.6) X IO "4 mM/h at 37°C, pH 7.0. The pseudo-zero order rate constant for the hydrolytic cleavage of a ribodinucleotide by the nitrate salt of the water soluble EuB2T2 texaphyrin has been examined. Investigations indicate that a 0.15 mM aqueous solution of Eu(B2T2 txph) 2+ hydrolytically cleaved uridylyl (3'→5') uridine, UpU, (0.49 mM) with a pseudo- zero order rate of (9.1 ± 1.6) x 10" 4 mM/h at 37°C, pH 7.0. In the absence of the metal complex no evidence of RNA cleavage was observed by HPLC. The reaction was followed by HPLC, monitoring the formation of uridine. Uridine-2'-monophosphate, uridine-3'-monophosphate, and uridine-2' :3'-cyclicmonophosphate (cUMP) were also observed by HPLC; this indicates a hydrolytic rather than an oxidative mechanism for the cleavage reaction. Uridine-2':3'-cyclicmonophosphate reached a steady state concentration, implying that the texaphyrin complex hydrolyzed cUMP as well. Under identical conditions, a 0.15 mM aqueous solution of Eu(N03)3 has a pseudo-zero order rate constant of 2.2 ± 0.35) x IO "4 mM/h. Therefore, small traces of free metal ions cannot account for the hydrolysis observed in the presence of the texaphyrin metal complex. Under these conditions, the Eu(III) complex of HAM displayed a pseudo-zero order rate constant of 4.1 x IO "4 mM/h. Thus, the texaphyrin complex is found to be more effective than the HAM system. A survey of other lanthanide (III) complexes of the B2T2 texaphyrin indicates that these complexes are also capable of RNA hydrolysis. Results are summarized in Table 2. TABLE 2 Rate Constants (Pseudo-Zero Order) for the Hydrolysis of UpU by Lanthanide (III) B2T2 Texaphyrin Complexes 3 LANTHANIDE CATION k i mM/h La(III) 1. . 16 X IO "4 Nd(III) 4 . . 69 X IO "4 Sm(III) 6 , . 3 X IO "4 EU(III) 4 . . 99 X IO "3 Gd(III) 1. . 44 X IO "4 Dy(III) 6. , 0 X IO "3 Tm(III) 4 . , 16 X IO "4 a The concentrations of the Lanthanide(III)B2T2 txph(N03) 2 are all approximately 0.25 mM. Further evidence supporting the catalytic effect of the texaphyrin metal complex was obtained by monitoring the formation of uridine produced from the Eu(T2B2Txp) +2 catalyzed decomposition of uridine- 2',3'-cyclicmonophosphate (cUMP) . The decomposition of cUMP (0.10 mM) catalyzed by Eu(T2B2Txp) +2 (0.15 mM) , when incubated at 37°C and pH=7.0 (5 mM HEPES buffer), had a pseudo-zero order rate of 6.94 x 10 "5 mMh "1 for the production of uridine. Examination of the reaction products by HPLC indicated that initially, cUMP is isomerized to uridine-3'-monophosphate (3'-UMP) and uridine-2'-monophosphate (2'-UMP) which are subsequently hydrolytically cleaved to produce uridine (Figure 14) . EXAMPLE 6 Generalized Hydrolysis of RNA Using a Texaphyrin Metal Complex This example describes the degradation of a homogenous population of RNA molecules with europium B2T2 texaphyrin. P 2 -labelled RNA transcripts from an isolated clone was the homogenous RNA substrate. The transcripts and their degradation products were visualized by polyacrylamide gel electrophoresis and autoradiography. pGEM®-3Z vector and Riboprobe® RNA transcript systems were obtained from Promega Corporation, Madison, Wisconsin. A 4.3 kb fragment of the mouse lb Multi Drug Resistant gene (MDR) was cloned into the .EcoRI site of the pGem 3Z vector and its orientation determined (see Fig. 5) . The plasmid was used in transcription reactions and when digested with -BamHI, T7 RNA polymerase makes a transcript from this template that is approximately 2000 bases long. The transcription reaction consisted of 100 ng of BamHI digested pGem 3Z/4.3 MDR#3, 20 μl of 5X transcription buffer, triphosphate nucleotides (A,C,G) at 500 μM, UTP at 100 μM, 50 μC of 32 -P α-UTP (3000 Ci/mmol) , 10 mmol DTT, 120 units of RNasin and 70-100 units T7 RNA polymerase. This reaction was brought up to a total volume of 100 μl with DEPC treated double distilled water. The reaction was allowed to incubate at 37° C for 1.5 hours. The entire reaction volume was then run over a G-50 Sephadex column (Nick column, Pharmacia) pre- equilibrated with 20 mM Tris pH 7.0, 2 mM EDTA, 0.1% SDS. The transcript was eluted from the column in the second 400 μl volume applied to the column. Any unincorporated nucleotide was left on the column. Ten μl aliquots of the transcript were put into separate tubes and stock solutions of Eu(III)B2T2txp I Q , EDTA or Eu(III) acetate were added so that the final volume was 20 μl. The tubes were allowed to incubate for 2 hr at 37°C. Thirty μl of dye mix (formamide, 0.2% bromphenol blue) was added to each tube. The tubes were mixed and heated at 60°C, 5 min, then the entire content of the reaction was loaded onto a 5% 8M urea polyacrylamide gel and electrophoresis was performed. The results of the digests of the 2000 base long transcripts with EuB2T2 txp are shown in Figure 7. There is one band in the control and control with EDTA lanes 1, 2 and 12. This band is absent in the lane with 100 μM EuB2T2 txp, lane 3. An increase in lower molecular weight material, i.e. degradation products, is seen as smearing throughout lane 3. The transcript remains intact at the lower EuB2T2 txp concentrations, lanes 4-7. The transcript is degraded with 100 μM EuB2T2 txp in the presence of 500, 300, 100 and 10 μM amounts of EDTA, lanes 8-10 and 13. This experiment eliminates the possibility that free metal in the B2T2 txp solution is causing the degradation. Lane 11 contains molecular weight standards of 1418 and 679 bases. Figure 6 shows that the 100, 50, 25, 10 and 5 μM concentrations of free Europium metal salt (EuOAc) do not digest the transcript, lanes 3-7. These results are not affected by the presence of EDTA, lanes 8-11. A digestion of total RNA (primarily 28s and 18s ribosomal RNA from K562 cells) with EuOAc, EuT2B2 txp and GdT2B2 txp indicated that all are able to hydrolyze total RNA. The digestions were performed in 50% DMSO and H 2 0, the gel was electrophoresed using a 10 μM phosphate buffer, pH 6.8. It is likely that EuOAc digests the homogeneous transcript also but at higher EuOAc concentrations than those used in the present example. Clearly, EuB2T2 txph is able to hydrolyze RNA substrates. Since the texaphyrins have such versatility for functionalization, this result has significant implications for the construction of site-specific cleaving reagents for nucleic acids and other molecules as discussed further in the following examples. EXAMPLE 7 Site-Specific Hydrolysis of RNA by Europium(III)-Texaphyrin Conjugated to a Synthetic Oligodeoxyribonucleotide The present example provides antisense agents using a texaphyrin metal complex-oligonucleotide conjugate that effects the hydrolysis of its RNA complement. Such antisense agents should therefore be able to act in vivo without the participation of endogenous nucleases. A DNA-EuTx-oligonucleotide conjugate was synthesized based on the functionalized texaphyrin 8 β , Figure 8, (2 F , Figure 2). This "ribozyme analogue" (cf., 8 C ) provides an example of oligodeoxynucleotide-directed, metal catalyzed hydrolysis of a complementary RNA oligomer. Two 20-mer oligonucleotides were machine-synthesized to contain alkylamine groups at either the 5-position of an internal thymine residue or the 5'-end terminal phosphate. Oligodeoxynucleotide-amines modified on the 5-position of thymine were purchased from Oligo's Etc. (Wilsonville, Oregon) ; oligodeoxynucleotide-amines modified on the 5' end were purchased from Keystone Laboratories, Inc. (Menlo Park, California) . Oligonucleotides were HPLC purified and precipitated using LiCl prior to use. Reaction of the carboxylic acid functionalized europium(III) texaphyrin complex 8 β with carbodiimide and N-hydroxysuccinimide produced the corresponding activated ester, which was added directly to a solution of the chosen oligodeoxynucleotide amine. The resulting DNA-EuTx conjugates (Figure 9, 9 A _ D ) were purified by electrophoresis. A synthetic RNA 30-mer (10 β , Figure 10) was obtained as substrate (Keystone Labs, Inc. , Menlo Park, California) , with a sequence selected from a unique site within the gene transcript for multiple drug resistance. Sequence is complementary at 1562 bases post- transcriptional start site in mouse multidrug resistance protein mRNA. The 3'- 32 P-labelled substrate was incubated with an excess of oligodeoxynucleotide conjugate at 37°C for 18-24 h in a buffered salt solution, ethanol precipitated, and assayed on a 20% denaturing polyacrylamide gel. As illustrated schematically in Figure 10 and shown in Figures 11A and 11B, ca. 30% cleavage occurred near the expected location of the europium (III) texaphyrin complex upon hybridization with conjugate 10^. Cleavage yield was measured by densitometry and calculated as ratio of cleavage band to intact material. The corresponding cleavage bands were not observed when this same substrate was incubated with oligonucleotides that were non- complementary in sequence, unmodified, or were modified internally with the complex (Figures 11A-11B, lanes 8- 10) . Control reactions indicate that ambient light, calf thymus DNA or type of buffer (Tris acetate or HEPES, EDTA, pH 6.0-8.0) had no apparent effect on cleavage efficiency. EDTA inhibits cleavage by free lanthanide (III) cations as observed in Morrow et al . (1992). Figures 12 and 13 demonstrate hydrolysis of 5'end labelled RNA 30-mer 10 B by EuTx-conjugate 10 A . Comparison of lanes 3-6 with lanes 7-14 of Figure 12 indicates that hydrolysis occurs more readily at 37°C than at 25°C. Lane 3 of Figure 13 demonstrates that a noncomplementary oligo 9 β does not effect hydrolysis of lO jj and lane 4 demonstrates that a conjugate having a complementary oligo and EuTx bound to an internal T residue does not effect hydrolysis of the RNA substrate. Lanes 5-9 demonstrate hydrolysis of the RNA substrate by 10 A , a 5' EuTx conjugate having an oligonucleotide complementary to substrate 10 B . The cleavage fragments co-migrate with bands in sequencing lanes produced by incubation of substrate under alkaline conditions or subjected to partial digestion with a series of base-specific ribonucleases (For an example of a similar end-product analysis, see Dange et al . , 1990). This observation is consistent with a hydrolytic mechanism, presumably involving the EuTx acting as a Lewis acid that facilitates an intramolecular attack of the 2'-hydroxyl group to effect cleavage. There are bands indicating site-specific cleavage of the ribonucleotide target sequence in the absence of any added cleavage reagents (lane 1, Figure 11A) . Although the source of this background cleavage is unknown, it is believed to be the direct result of a higher order structure (ie., a hairpin) of the oligoribonucleotide, since hybridization with any complementary oligonucleotide dramatically inhibits the cleavage (eg. , lanes 2, 5-7, 9, Figure 11A) . This type of structure- dependent cleavage behavior has been seen previously with oligoribonucleotides (Dange et al., 1990, Kazabov et al . , 1992) . Maximal cleavage activity of the Eu(III)Txp- oligonucleotide was observed down to 25 nM conjugate. Decreased cleavage below this level may be due to a decrease in hybridized material (as judged by increased background cleavage of the target RNA present at a concentration of about InM) . By means of comparison, the free europium complex non-specifically hydrolyzed the RNA substrate at 25 μM (lane 4, Figure 11A) . In the control reaction containing both complex and the non-derivatized complementary DNA oligomer (lane 7, Figure 11A) , cleavage occurred predominantly in the single stranded region, although still at lower efficiency than the Eu-Tx-DNA conjugate at 2.5 nM. Thus, attachment of the EuTx to the DNA probe increases its effective concentration ca. 10,000-fold. A target RNA without the secondary structure observed here would likely allow for cleavage at lower DNA-EuTx concentrations. These data indicate the utility of such conjugates in antisense applications. As demonstrated in the present example, the selectivity of the texaphyrin complexes is enhanced by covalently linking oligonucleotides onto the periphery of the macrocycle. Since the metal complexes do cleave RNA over DNA preferentially, the DNA appendages would remain intact during the hydrolysis experiments. The DNA arm will recognize and bind to an appropriate RNA segment, effectively increasing the metal concentration at these loci relative to the overall metal concentration in solution. Phosphate ester hydrolysis will therefore be significantly increased at specific locations along the RNA backbone. In one embodiment, primers (known or deduced) for PCR could be coupled to a hydrolytic divalent or trivalent texaphyrin complex to induce hydrolysis of proximal RNA. Enhancement of RNA hydrolysis by the texaphyrin metal complex-conjugate may be accomplished by designing the deoxyribonucleotide to bind to the RNA target so as to produce a single-stranded loop which may have increased susceptibility to hydrolysis. The loop may contain one or more nucleotides. In this case, the oligodeoxyribonucleotide acts as a catalytic group by using the energy of its binding to the RNA target to increase the ground state energy of the targeted phosphate diester. Examples are illustrated in Figs. 18A and 18B. Fig. 18A shows a DNA twelve-mer lacking a nucleotide to base pair with the looped out "U" and conjugated at its 5' end to a Dy(III) texaphyrin complex. Binding to the RNA substrate causes a one-base loop structure that is a site of enhanced susceptibility to hydrolysis by the Dy(III)Txp complex. Fig. 18B shows a DNA ten-mer lacking the same nucleotide, conjugated to a Dy(III)Txp at its 3' end and to a second Dy(III)Txp at its 5' end, binding to the RNA substrate so as to cause the same one-base loop structure. The loop is a site of enhanced susceptibility to hydrolysis, this time by the two Dy(III)Txp complexes which converge on the loop structure upon binding. In this example, one Dy(III)Txp may act as a general acid and the second may act as a general base via a Dy(III)Txp-bound hydroxyl group for activating the RNA towards hydrolysis. EXAMPLE 8 Site-Specific Hydrolysis of RNA by Dysprosiu (III)- Texaphyrin and Europium (III) Texaphyrin Conjugated to synthetic Oligodeoxyribonucleotides of Varying Lengths Following the procedures of Example 7, oligodeoxyribonucleotide-amines of varying nucleotide lengths and modified at the 5' end (obtained from Keystone Labs, Menlo Park, California) were reacted with carboxylic acid functionalized dysprosium(III)-texaphyrin complex 8 β to give DyTx oligo-conjugates 9 F - 9 (Figure 9) . Corresponding EuTx oligo-conjugates were also prepared. Each of the above-described conjugates was then incubated with the 3'-labeled synthetic RNA 30-mer 10 β following the procedures of Example 7. All of the conjugates having complementary DNA and a texaphyrin complex at either end of the oligo hydrolytically cleaved the RNA, although the RNA was hydrolyzed by the Dy conjugates at about twice the rate (producing ca. 60% cleavage of the RNA) as by the Eu conjugates (Figure 22) . At the 250 nM concentration of DNA used, the 12-mer conjugate was found to be as effective as the 20-mer conjugate, the 9-mer conjugate was less effective and only a small amount of cleavage was observed with the EuTx-9 mer conjugate. Increased background cleavage of the RNA substrate in the presence of the 9-mer conjugate indicates that less specificity for annealing to the substrate is provided by the shorter oligonucleotide. These data indicate that oligonucleotides having as few as 12 bases provide the specificity needed for accurate and full hydrolytic activity. This aspect is important for drug design, since the ability of an oligonucleotide analog to traverse a cellular membrane is generally found to be inversely proportional to its length. EXAMPLE 9 Site-specific Hydrolysis of a 36-Mer RNA by Dysprosium (III)-Texaphyrin Conjugated to a Synthetic Oligodeoxyribonucleotide A 3'-labelled synthetic RNA 36-mer IOJJ (Promega Corp. , Madison, WI) (Fig. 10) was incubated with an excess of the DyTx-oligo conjugate 10 (9J) , following the procedures of Example 7, and the hydrolysis observed. As illustrated schematically in Figure 10, the DyTx-oligo conjugate hydrolyzed the RNA at positions indicated by the arrows. This additional result supports the breadth of utility for the texaphyrin-oligonucleotide conjugates in the hydrolysis of ester bonds. EXAMPLE 10 Synthesis of Texaphyrin-oligonucleotide Conjugates Having a Texaphyrin Attached to the 3' end of the Oligonucleotide Two oligodeoxyribonucleotides of 12 bases each were synthesized to contain alkylamine groups at the 3' terminal phosphate (Keystone Labs, Menlo Park, California) . These oligomers were reacted with carboxylic acid functionalized Eu(III)-texaphyrin complex 8g or Lu(III)texaphyrin complex following the procedures of Example 7, to give conjugates 9 j , 9 K and 9 N (Fig. 9). These 3'-conjugates may be of particular importance in certain embodiments of the present invention, since attachment of large groups (such as the present texaphyrin complexes) to the 3' end of oligonucleotides renders the oligonucleotide resistant to cellular nucleases. In a similar manner, an embodiment of the present invention is the addition of particular ligands to the 3' end of an oligonucleotide having its 5' end conjugated to a texaphyrin. The function of the 3' ligand is to aid in the uptake of the conjugate into the cell. Such ligands are known in the art and include, but are not limited to, cholesterol and polylysine. A further embodiment of the present invention in the hydrolysis of RNA using texaphyrin metal complex- oligonucleotide conjugates is the use of a set of two conjugates, one having the texaphyrin metal complex conjugated to the 5' end of an oligomer and the other having a texaphyrin metal complex conjugated to the 3' end of an oligomer and the oligomers are complementary to the same RNA substrate, one just upstream from the other, so as to position both texaphyrin metal complexes in proximity to the targeted hydrolysis site as depicted in Figure 21. The distance separating the two catalytic groups may be varied by preparing a nested set of oligomer-5'-conjugates of varying lengths and comparing the hydrolysis efficiencies that result upon the simultaneous binding of the two conjugates to the RNA template. EXAMPLE 11 Synthesis of an Eu(III) Texaphyrin-oligonucleotide Dual Conjugate An oligodeoxyribonucleotide having 12 bases was synthesized to contain alkylamine groups at both the 3' and the 5' ends (Keystone Labs, Menlo Park, California) . This oligomer was reacted with an excess of the carboxylic acid functionalized Eu(III)-texaphyrin complex 8JJ, following the procedures of Example 7, to give the dual conjugate 9^ (Fig. 9) which has an Eu(III)Tx metal complex at both the 3'- and the 5'-ends of the 12-mer. The use of two texaphyrin-metal complexes conjugated to the same oligonucleotide, one at each end, should effect the hydrolysis of RNA with increased efficiency due to the concerted activity of the metal complexes. In this embodiment, it is preferred that both of the texaphyrin complexes contain the same metal, preferably a lanthanide metal cation and more preferably europium(III) or dysprosium(III) . One of the texaphyrin metal complexes may act as an acid and the second may act as a base in order to further activate the RNA towards hydrolysis. Further, a dual conjugate provides versatility in the functions that may be accomplished by this one molecule. For example, the oligonucleotide provides binding specificity, one texaphyrin metal complex may provide for imaging (having Gd(III) as the metal ion, for example) while the other provides for ester hydrolysis. Such a dual conjugate allows for 2 functions, imaging and hydrolysis to be effected by one molecule. The use of texaphyrin metal complexes to cleave RNA in vivo as a treatment procedure relies on the effective localization of the complex to the site of desired cleavage. A site of desired cleavage may be a position novel to undesired organisms in terms of health care. A site of desired cleavage may be a messenger RNA encoding a product deleterious to the host or may be a normal RNA that is deleterious in some way. The data of Examples 6 through 11 demonstrate that lanthanide texaphyrin complexes may be developed into RNA antisense reagents. The anti-sense approach is efficient in regulating the expression of proteins. Many copies of a particular polypeptide are made from one messenger RNA molecule; therefore, by moving up in the levels of cellular processes and knocking out the message, fewer attacking agents would be required because there would be fewer target sites. The anti-sense strategy provides a clear and rational method for new drug design because there is one requirement, that the anti-sense probe hybridize to its target molecule. The hybridization requirement is very well understood via complementary Watson-Crick base pairing. Unlike the present methods in the art which require screening of thousands of compounds and X-ray crystal structure analysis, the information needed for anti-sense technology is the sequence of the target. Treating native RNA with this new texaphyrin complex results in the texaphyrin complex binding to a complementary RNA sequence via an appended oligonucleotide. The lanthanide texaphyrin complex then cleaves the RNA proximal to this specific site. Either one or two texaphyrin molecules may be attached to the DNA, creating the potential for gene splicing reagents. The texaphyrin oligo complex would have immediate applications for anti-viral and anti-bacterial therapy as well as cancers (an oligonucleotide complementary to an oncogene, for example) and inflammatory responses that are caused by the overexpression of certain proteins. Antisense technology is discussed in U.S. Patents 5,194,428, 5,110,802 and 5,216,141, all of which are incorporated by reference herein. EXAMPLE 12 Texaphyrin-Sapphyrin Conjugates for Ester Cleavage and Transport Across Membranes A further means of gaining selectivity is to link covalently the texaphyrin complex to a sapphyrin (sap) molecule, (Sessler et al . , 1992; Furuta et al . , 1991; Sessler et al . , 1991; U.S. Patent 5,159,065; U.S. Patent 5,120,411; U.S. Patent 5,041,078, all incorporated by reference herein) . Since sapphyrins bind phosphate, K = 20 M "1 in water at pH 7, the linked texaphyrin-sapphyrin complex (txph-sap) could effectively increase the metal concentration at locations adjacent to the sapphyrin binding sites. Since the txph-sap molecule would be quite large it is expected that the ternary structure of RNA will provide a limited number of favorable binding sites. Thus, a degree of structural selectivity for RNA hydrolysis would be expected, with this selectivity being based on the conformations of the substrate molecules. The synthesis of (Eu) texaphyrin-sapphyrin conjugate (Figures 15 and 16) : Synthesis was accomplished by amide bond formation between activated (Eu)texaphyrin carboxylic acid and amino-substituted sapphyrin. By the same strategy, a variety of texaphyrin-sapphyrin conjugates may be prepared including conjugates where other metallic cations may be incorporated into the texaphyrin moiety. Figure 15 shows the formation of exemplary amide linked derivatives of texaphyrin. The synthesis of (Eu) texaphyrin acid EuT2Bl (0 (CH 2 ) 3 CO^I) 16 β , R = CH 2 0H, Figure 16. Texaphyrin derivative (T2B1(0(CH 2 ) 3 C0 2 H) «HC1, 0.694g, lmmol) was dissolved in 80 ml of dry methanol. Eu(OAc) 3 .H 2 0 (0.329 g, lmmol) was added, followed by triethylamine (0.5 ml). The reaction mixture was refluxed (reflux condenser was open to the air) for 6 hours, with the progress of metallation followed by visible spectra. Methanol was evaporated under reduced pressure to give a dry, dark solid which was washed with dichloromethane under vigorous stirring for 2 hours. The product was filtered off, redissplved in MeOH (25 ml) , and the solution was treated with zeolite (by standard procedure for removing free europium salt) . The product was twice precipitated from methanol by adding diethylether. The collected dark green solid was dried under high vacuum overnight. Yield 91.0%. Characterization data: Elemental analysis for C 38 H 44 N 5 0 5 Eu«2(OAc) (F.W. 920.855) calc. 54.78% C, 5.47% H, 7.61% N; found 54.46% C, 5.50% H, 7.55% N. FAB HR MS: For C3 8 H 4 3N 5 0 5 Eu calc. 802.24626; found 802.247752. UV-Vis (EtOH, λ j na,-) : 420, 469, 760 nm. The Synthesis of EuTexaphyr in- Sapphyrin derivative (16 c , Figure 16) : Texaphyrin dihydroxyl, carboxylate derivative as described above (0.092 g, 0.1 mmol) was dissolved in 10 ml dry dimethylformamide (solvent without dimethylamine) . The solution was cooled on ice to 0°C. The activating agent (carbodiimide, EDC, 95.5 mg, 0.5 mmol) and hydroxybenzotriazole (5 mg) were added and the mixture was held at 0°C for 45 minutes. For the preparation of the aminosapphyrin derivative 16 A , the sapphyrin monocarboxylic acid was, after activation with DCC, reacted with t-BOC monoprotected ethylenediamine and then subsequently deprotected by treating with TFA at room temperature for 1 hour. The solution of aminosapphyrin derivative 3,8,17,22-tetraethyl-12-[N-(2- aminoethyl)aminocarbonylethyl-2,7,13 ,18 ,23- pentamethylsapphyrin (16 A 0.067 g, 0.1 mmol) in 5 ml of dimethylformamide and 0.1 ml of dry pyridine was added at the same temperature. The reaction mixture was kept at 0°C for 30 minutes, allowed to warm to room temperature, and stirred for 3 days. Solvent was evaporated under reduced pressure. The crude product was washed, dissolved in EtOH (10 ml) and diethylether was slowly added. Precipitated product was dried in vacuo . Yield 68%. Characterization data: UV-Vis λ^-. (EtOH): 358, 431, 450, 618, 681, 761 nm. (H 2 0, pH7) : 358, 408, 455, 623, 675, 765 nm. FAB MS: For Cg Q Hp j N j ^Eu calc. 1456.67539; found 1457. Alternative synthetic approaches to analogous heterodimers may include the coupling of amino- substituted texaphyrins (prepared by the reaction of texaphyrin carboxylate anion with monoprotected ethylenediamine H 2 N(CH 2 ) 2 NHR, where R is (CH3) 3 COCO-(t- BOC) , followed by heating to 180°C to effect deprotection) with activated sapphyrin monocarboxylic acid derivatives (e.g., sapphyrin acid chloride, or the products obtained from treatment with dicylohexylcarbodiimide, DCC) . This compound 16Q was tested (a) for transport of ADP and ATP across bulk liquid membrane. Efficient transport at neutral pH was observed, and (b) phosphodiester hydrolysis - during ATP transport, AMP was formed as a result of hydrolysis. Transport studies were performed using an H 2 0-CH 2 C1 2 -H 2 0 three phase Pressman- type U-tube type model membrane system (Araki et al . , 1990) . Aqueous phase I (source phase) was 5 mM solution of ADP, ATP at pH 7.0, the organic phase was 0.1 mmol solution of (Eu)texaphyrin-sapphyrin conjugate. Aqueous phase II (receiving phase) was water, pH 7.0. The increase in concentration of ADP and ATP in the receiving phase as a result of membrane transport was followed as a function of time. Quantities transported were determined by HPLC analysis of receiving phase using cytosine and/or adenosine as the internal standard(s) (reverse phase analytical column, 10 mM phosphate buffer, pH 5.6). In this way the initial transport rates for the through- membrane transport of ADP and ATP were derived. Results show that the initial rate of transport for ADP is in range of 5 x IO "9 mol/cm 2, h and about five times lower than this for ATP. During the course of the above-described through-membrane transport of ADP and ATP the formation of a new compound in the receiving phase, determined to be AMP by comparison with an authentic sample, was also observed. Since this AMP material was not present in the source phase nor observed when carrier-free control experiments were carried out, its production as the result of the (Eu)texaphyrin-sapphyrin conjugate mediated transport process is taken as indicating that the conjugate is capable of effecting the hydrolysis of a phosphodiester bond. Texaphyrin-sapphyrin conjugates or analogs thereof should be very useful in antisense applications: Sapphyrin binds to phosphate diesters, such as those of DNA, with high specificity and affinity. Ln(III) texaphyrins bind to anionic phosphates and effect the hydrolytic cleavage of RNA and related species. Thus, a texaphyrin-sapphyrin conjugate should provide an enhanced recognition of RNA/DNA and an improved rate of hydrolysis by virtue of the induced "neighboring group effect". Along with the potential to cleave RNA specifically the texaphyrin molecule may be designed to pass through cell membranes and selectively attack viral RNA. Such a molecule would have the potential to treat human patients infected with a variety of viruses, including HIV, and to treat blood in vitro or ex vivo for viral infection to purge or purify blood. EXAMPLE 13 Synthesis of a Dy(III)-Texaphyrin Having an Imidazole Catalytic Group, Figures 19A-19B Dysprosium (III) complex of 16- [1- (hydroxy) acet 1-2- oxyl-17- [2- [2- [2- [2- (N-imidazolyl) ethoxy]ethoxy]ethoxy] ethoxy ] -9 , 24-bis (3 -hydroxy propyl) -4 , 5-diethyl-10 ,23- dimethyl-13 ,20 , 25,26, 27-pentaazapentacyclo- [20.2.1.1 3 ' 6 .1 8 ' 11 .0 14 ' 19 ]heptacosa- 1,3, 5, 7, 9, 11 (27) , 12, 14 (19) , 15, 17,20,22 (25) ,23-tridecaene (19JJ, Fig. 19B) . 4,5-Dinitrocatechol (19 A ) is reacted with triethylene glycol ditosylate (1 equiv.) in the presence of potassium chloride and methanol. The monotosylate (19 B ) is isolated from the resulting mixture, and is reacted with imidazole (1 equiv.) in the presence of potassium carbonate and methanol to give 4,5- dinitro-2-[2-[2-[2-[2-(N-imidazolyl)ethoxy]ethoxy]ethoxy] ethoxy]phenol (19 ) . Following the procedures described for the synthetic scheme of Figure 2A, and as outlined in Fig. 19A-19B, compound 19^ is reacted with ethyl-2- iodoacetate, and the resulting compound 19 D is saponified and reduced to give the corresponding diamino compound 19 E which is then reacted with tripyrrole 19p. The resulting nonaromatic macrocycle 16-[1-(hydroxy)acetyl-2- oxy]-17-[2-[2-[2-[2-(N-imidazolyl)ethoxy]ethoxy]ethoxy] ethoxy]-9,24-bis(3-hydroxypropyl)-4,5-diethyl-lO,23- dimethyl-13,20,25,26,27-pentaazapentacyclo- [20.2.1.1 3 ' 6 .1 8 ' 11 .0 14 ' 19 ]heptacosa- 3,5,8,10,12,14(19) ,15,17,20,22,24-undecaene (19Q) is metallated to give the Dy(III)Tx complex 19 H having an imidazole as a catalytic group. The above-described Dy(III)-Tx complex is an example of a texaphyrin complex having an appended catalytic group, imidazole, attached via a tri(ethylene glycol) linker to a texaphyrin metal complex. Such a catalytic group may assist as a general base in site-specific hydrolysis of an RNA target. For this purpose, the texaphyrin metal complex is conjugated to an oligodeoxyribonucleotide complementary in sequence to the RNA being cleaved. The oligo is conjugated to the texaphyrin via a linker group, such as the carboxy group at the 16-position of the Dy(III)Tx compound 19 H , following the procedures described herein. EXAMPLE 14 Synthesis of Eu(III)-Texaphyrin Having an Amino Acid or Amino Acid Derivative Catalytic Group Eu(III)-Tx carboxylic acid complex 2p (n=3, 92 mg, 0.1 mmol) was dissolved in 5 mL of dry purified DMF and cooled to 0°C, after which l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC; 57 mg, 0.3 mmol) and 0.5 mL of pyridine were added. The resulting activation reaction was allowed to proceed for 1 hr at 0°C. Histamine dichloride (55 mg, 0.3 mmol) was then added, together with 1-hydroxybenztriazole (5 mg) and dimethylaminopyridine (5 mg) in 3 mL of water. The reaction mixture was then stirred for l hr at 0°C, followed by stirring at RT for 5 days. The solvents were evaporated off in vacuo at RT and the product was recrystallized from a methanol-benzene mixture to give the final Eu(III)Tx-histamine conjugate shown in Fig. 20A. An analytical sample was prepared by reverse phase column chromatography. UV-Vis (H 2 0, pH 7) : X j ^^ (nm) : 457.5, 761.5; FAB HR S: for C 43 H 51 N 8 0 4 Eu, calcd.: 896.324571, found: 896.323476. Following the above-described procedures, L-arginine methyl ester dihydrochloride (78 mg, 0.3 mmol) was reacted with the activated Eu(III)Tx carboxylic acid 2p. The reaction mixture was stirred for 1 hr at 0°C and then for 5 days at RT. The solvents were evaporated off and the product recrystallized to give the final Eu(III)Tx shown in Fig 20B. UV-Vis (H 2 0, pH 7): λ ma (nm) : 457.0, 761.0; FAB HR MS: for C^^gCINgOgEu, calcd.: 1008.341102, found: 1008.34004. Following similar procedures, metal complexes of texaphyrin having substituents containing an amine group may be prepared via reaction of the activated acid of the texaphyrin complex with an amine component of the amine- containing substituent. Fig. 15 presents a general synthetic scheme. These amine substituents may function as catalytic groups to assist the texaphyrin metal complex in catalyzing ester hydrolysis. Amine-containing substituents include amine-containing saccharides, polysaccharides, amino acids, amino acid derivatives, polyamino acids and the like. EXAMPLE 15 Texaphyrin-Texaphyrin Conjugates (Fig. 17) Texaphyrins may be coupled to form a texaphyrin- texaphyrin conjugate similar to the texaphyrin-sapphyrin conjugate described in Example 12. A carboxylate texaphyrin derivative may be converted to an amino derivative by coupling with diamino compounds, such as NH 2 (CH 2 ) n NH 2 , or by coupling with a monoprotected compound of the type NH 2 (CH 2 ) n NHR, where R may be a variety of protecting groups and n is an integer from 1 to 7, preferably from 1 to 3. The individual TX metal complex in a texaphyrin-texaphyrin conjugate may have the same or a different chelated metallic cation from the other TX metal complex. Fig. 17 shows a texaphyrin-texaphyrin conjugate which is prepared by the reaction of 2 equivalents of a metallotexaphyrin (such as Eu-TX) carboxylic acid with an activating reagent, e.g. EDC, followed by coupling with an amino component, for example, ethylenediamine. Texaphyrin metal complexes, especially paramagnetic metal complexes, bind phosphate anions, nucleotides and oligonucleotides as indicated by up to 200 pp shifts in 1 HNMR spectra induced by the binding of these compounds. The apparent association constant for formation of a monoadduct with diphenylphosphate monoanion in 1 methanol/chloroform is 290 dπr mol "1 and for formation of a diadduct is 74 dnr mol "1 . Similar changes in spectral patterns were observed from binding of phenyl phosphate dianion, phenylphosphonate monoanion, uridine 5'- monophosphate, uridine 2',3'- monophosphate, guanosine 5'- monophosphate and oligonucleotide mixtures. The lanthanide adducts of texaphyrin-texaphyrin conjugates may be useful for effecting hydrolysis of di- or triphosphate species such as ATP, hydrolysis at multiple sites in a phosphate polyester, such as RNA or for effecting simultaneous binding and hydrolysis of such RNA -type substrates. For MRI and PDT, a combined diamagnetic/paramagnetic species would allow for binding, imaging and dual cleavage possibilities via hydrolysis and photo-activation. The use of two proximal texaphyrins should effect the hydrolysis of RNA with increased efficiency due to the concerted activity of the metal complexes. For example, one complex may act as a Lewis acid while the second serves to generate a metal-bound hydroxide general base at neutral pH. Similar mechanisms have been proposed based on crystallographic data obtained from single crystals of DNA hydrolyzing enzymes such as the 3'-5' exonuclease activity of DNA polymerase. EXAMPLE 16 Further Uses for Lanthanide Texaphyrins Coupled to Site-Directed Molecules U.S. Patent 5,252,720 describes magnetic resonance imaging experiments with B2T2 gadolinium complex in vivo . The results show that the B2T2 gadolinium complex demonstrates in vivo affinity for tissue high in lipid content, atheroma, the liver, kidneys and tumors, and has low toxicity in rodents. As exemplified herein, the chemical properties of this texaphyrin class of macrocyclic ligands can be varied by peripheral substitution, which allows biological properties to be optimized in terms of biodistribution, pharmacokinetics and toxicity. Texaphyrin metal complexes are especially suited for acting as bifunctional chelating agents in a variety of targeted treatment regimens. Texaphyrin-metal complexes are effective in antibody conjugate-based treatment since they have functional groups suitable for conjugation to the antibody. They form covalent linkages that are stable in vivo which do not destroy the immunological competence of the antibody, they are relatively nontoxic, and they are readily soluble in a physiological environment. A further advantage of these texaphyrins is that many would be suitable for further functionalization. Treatment of carboxylated texaphyrins with thionyl chloride or p-nitrophenol acetate would generate activated acyl species suitable for attachment to monoclonal antibodies or other biomolecules of interest. Standard in situ coupling methods (e.g. 1,1'- carbonyldiimidazole (CDI) ) could be used to effect the conjugation. Many cell membranes are partially constructed from phospholipids. Thus, lanthanide texaphyrins may be developed into synthetic specific phospholipases. One skilled in the art in light of the present disclosure could then determine precisely the lipid side chain that is connected via the phosphate ester bond in a given phospholipid. An extension of this process would be to digest cell membrane components such as phosphatidyl choline and sphingomyelin. This is important since the latter participates in nerve and brain functions. The development of potent cytotoxins from lanthanide texaphyrins may be accomplished by developing reagents that specifically hydrolyze ATP, ADP, NADH, or FADH 2 . Said cytotoxins may disrupt, in a biologically specific way, the flow of free energy in the cell and essentially starve the organism. This could allow for the death of undesired plants and animals or the treatment of mammalian cancers. Liver diseases causing the accumulation of glycogen may be treated by hydrolyzing uridine diphosphate glucose (UDP) , the phosphodiester precursor to glycogen. The present invention demonstrates that uridine phosphates are hydrolytically cleaved by lanthanide texaphyrins and previous work with texaphyrin (U.S. Patent 5,252,720) has shown that they localize in the liver. Thus, one skilled in the art would realize that the basic features of this approach have already been demonstrated by experiment. Cyclic adenosine monophosphate (cAMP) is believed to play an important part in regulating various hormones. Hydrolyzing cAMP to the linear adenosine monophosphate (AMP) impedes certain hormone regulation. Texaphyrin complexes may therefore be used as hormone regulation drugs. A further use for texaphyrin metal complexes may be as hydrolysis reagents for the detoxification of di- and trialkyl phosphate esters. Alkyl phosphate esters have a wide range of uses including solvents in chemical reactions, insecticides (e.g., parathion) and chemical nerve gases (e.g., diisopropyl phosphofluoridate, DIPF) . Hydrolysis and detoxification of these agents in the environment is often slow by natural processes. Developing catalysts for the hydrolysis of alkyl phosphate esters could greatly improve the lives of many people. Texaphyrin complexes could further be developed as treatment for patients that have been exposed to such nerve agents. Here, the key feature is that texaphyrins are known to hydrolyze phosphate esters quickly. The following references are incorporated in pertinent part by reference herein for the reasons cited below. REFERENCES Agrawal, S., and Tang, J.Y., Tetrahedron Letters , 31:7541, 1990. Araki, T. et al . , Liquid Membranes: Chemical Applications , CRC Press, Boca Raton, 1990. Basile, L.A. et al., J. Am . Chem. Soc , 109:7550, 1987. Breslow, Ronald and Huang, Deeng-Lih, Proc. Natl . Acad . Sci . USA, 88:4080, 1991. Browne, Kenneth A. and Bruice, Thomas C, J. Am . Chem . SOC , 114(13) :4951, 1992. Chin, Jik and Banaszczyk, Mariusz, J. Am . Chem . Soc , 111:4103-4105, 1989. Chin, Jik and Banaszczyk, Mariusz, J. Am. Chem. Soc, 111:2724, 1989. Chin, Jik et al. J. Am. Chem. Soc, 111:186-190, 1989. Chin, Jik and Zou, Xiang, Can J. Chem., 65:1882, 1987. Dange, et al., Science, 248:585-588, 1990. Eichhorn, G. L. ; Butzow, J. J. Biopolymers , 3:79-94, 1965. England, T. E. ; Uhlenbeck, O. C. Biochemistry, 17:2069- 2076, 1978. Furuta et al., J. Amer. Chem. Soc, 113:6677, 1991. Hayashi, N. , et al., Inorg. Chem., 32:5899-5900, 1993. Hendry, Philip and Sargeson, Alan M. , J. Amer. Chem. SOC, 111:2521, 1989. Kazakov, S.; Altman, S. Proc Natl. Acad. Sci. USA 89:7939-7943, 1992. Kim, Jung Hee and Chin, Jik, J. Am. Chem. Soc, 114:9792- 9795, 1992. Kolasa, et al., Inorg. Chem., 32:3983-3984, 1993. Komiyama, Makoto et al., J. Chem. Soc, Chem. Commun. , pp. 640-641, 1992. Kuchino, Y. Methods in Enzymology, 180:154-163, 1989. Menger, F.M. et al., J. Am. Chem. Soc, 109:2800, 1987. Modak, Anil S. et al., J. Am. Chem. Soc, 113:283, 1991. Morrow, J.R. et al., J. Am. Chem. Soc, 114:1903, 1992. Morrow, et al., Inorg. Chem., 32:4566-4572, 1993. Ranganathan, Darshan et al., J. Chem. Soc, Chem. Commun. , 4:337, 1993. Schneider, et al., Angew. Chem. Int. Ed. Engl., 32:1716- 1719, 1993. Sessler et al., Synlett, pp. 127, 1991.. Sessler, J.L. and Burrell, A.K. , Top. Curr. Chem. Rev., 161:179, 1991. Sessler et al., Tetrahedron, 48:9661, 1992. Shelton, Valerie and Morrow, Janet R. , Jno-rgr. Chem., 30:4295, 1991. Stern, Michael K. et al., J. Am. Chem. Soc, 112:5357, 1990. Sumaoka Jun et al., J. Chem. Soc. Chem. Commun., pp. 1707-1708, 1992. Chung, Yongseog et al., Tetrahedron Letters, 31:5413, 1990. U.S. Patent 5,159,065. U.S. Patent 5,120,411. U.S. Patent 5,041,078. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANTS: NAME: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM STREET: 201 West 7th Street CITY: Austin STATE: Texas COUNTRY: United States of America POSTAL CODE: 78701 TELEPHONE NO: (512)499-4462 TELEFAX: (512)499-4523 NAME: PHARMACYCLICS, INC. STREET: 995 East Arques Ave. CITY: Sunnyvale STATE: California COUNTRY: United States of America POSTAL CODE: 94086-4593 TELEPHONE NO: (408)774-0330 TELEFAX: (408)774-0340 (ii) INVENTORS: SESSLER, Jonathan L. SMITH, Daniel A. MILLER, Richard ROSS, Kevin WRIGHT, Meredith HEMMI, Gregory W. DOW, William C. KRAL, Vladimir IVERSON, Brent MAGDA, Darren MODY, Tarak (ϋi) TITLE OF INVENTION: TEXAPHYRIN METAL COMPLEX MEDIATED ESTER HYDROLYSIS (iv) NUMBER OF SEQUENCES: 16 (V) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Arnold, White & Durkee (B) STREET: P.O. Box 4433 (C) CITY: Houston (D) STATE: Texas (E) COUNTRY: USA (F) ZIP: 77210 (vi) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS/ASCII (vii) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: UNKNOWN (B) FILING DATE: CONCURRENTLY HEREWITH (C) CLASSIFICATION: UNKNOWN (vϋi) PRIOR APPLICATIONS DATA: (A) APPLICATION NUMBER: USSN 08/075,123 (B) FILING DATE: 09 JUNE 1993 (09.06.93) (C) CLASSIFICATION: UNKNOWN (A) APPLICATION NUMBER: USSN 08/227,370 (B) FILING DATE: 14 APRIL 1994 (14.04.94) (C) CLASSIFICATION: UNKNOWN (ix) ATTORNEY/AGENT INFORMATION: (A) NAME: PARKER, DAVID L. (B) REGISTRATION NUMBER: 32,165 (C) REFERENCE/DOCKET NUMBER: UTFB570P— (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 512/320-7200 (B) TELEFAX: 713/789-2679 (B) TELEX: 79-0924 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE, nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: CTCGGCCATA GCGAATGTTC 20 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: CATCTGTGAG CCGGGTGTTG 20 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GAACAUUCGC UAUGGCCGAG AAGAUGUCAC C 31 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: GAACAUUCGC UAUGGCCGAG AAGAUG 26 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: CTCGGCCATA GC 12 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: CTCGGCCAT (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: ATAGCGATGT TC 12 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: GAACAUUCGC UAUGGCCGAG AAGAUGUCAC 30 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: ATAGCGATGT 10 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: TAGCGAATCT TTC 13 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 36 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: RNA (genomic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: ACACACCCGG CUCACAGAUG AAGUCUCCAA AAUAAA 36 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: CTGTGAGCCG GGTGTTG 17 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13 TTTATTTTGG AGACTT 16 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14 TGTGACGGGG GTGTTG 16 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: TCTGTGAGCC GGGTGTTG 18 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: ATCTGTGAGC CGGGTGTTG 19

Claims: CLAIMS 1. A method of phosphate ester hydrolysis, the method comprising: obtaining an aqueous phosphate ester solution, and incubating the solution with a texaphyrin metal complex having catalytic activity for ester bond hydrolysis, said incubation being under conditions and for a time sufficient to hydrolyze the phosphate ester. 2. The method of claim 1 where the texaphyrin metal complex has the structure: where: M is a divalent or a trivalent metal cation catalyzing ester bond hydrolysis in aqueous solution; R 1# R 2 , R 3 , R 4 , R5 and ^ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, saccharide, carboxyalkyl, carboxyamidealkyl, a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group; and N is an integer less than or equal to 2. 3. The method of claim 1 or 2 wherein the phosphate ester is RNA. 4. The method of claim 2 wherein at least one of R j , R 2 , R3, R 4 , R5 and Rg is a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group. 5. The method of claim 4 wherein the catalytic group is imidazole, guanidine, an amino acid, an amino acid derivative, a polyamino acid, an amine-substituted saccharide or a texaphyrin metal complex. 6. The method of claim 4 wherein the site-directed molecule is an oligonucleotide, a hormone, an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule. 7. The method of claim 4 wherein the site-directed molecule is an oligonucleotide. 8. The method of claim 4 wherein the site-directed molecule is an oligodeoxyribonucleotide. 9. The method of claim 4 wherein the site-directed molecule is an oligonucleotide conjugated to a catalytic group. 10. The method of claim 9 wherein the catalytic group is a texaphyrin metal complex. 11. The method of claim 7 wherein the oligonucleotide has complementary binding affinity for oncogenes. 12. The method of claim 7 wherein the phosphate ester is RNA and the oligonucleotide has complementary binding affinity for the RNA in a region proximal to the phosphate ester bond being hydrolyzed. 13. The method of claim 7 wherein the oligonucleotide has complementary binding affinity for a targeted intracellular mRNA. 14. The method of claim 4 wherein one of R3, R5, and R^ is an oligonucleotide or a couple to an oligonucleotide. 15. The method of claim 2 wherein R j is (CH 2 ) CH 2 OH, R 2 and R 3 are CH 2 CH 3 , R 4 is CH3 and R 5 and Rg are OCH 2 CH 2 CH 2 OH. 16. The method of claim 2 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and R 3 are CH 2 CH 3 , R 4 is CH3, R5 is a site-directed molecule, a catalytic group, or a couple to a site- directed molecule or to a catalytic group and Rg is H. 17. The method of claim 16 wherein R5 is 0(CH 2 ) n CO- oligonucleotide where n is 1-7. 18. The method of claim 2 wherein R is (CH 2 ) 2 CH 2 OH, R 2 and are CH 2 CH3, R 4 is CH3, R5 is a (couple) t -site directed molecule-catalytic group conjugate where t is zero or 1 and R-g is H. 19. The method of claim 18 wherein R5 is 0(CH 2 ) n CO- oligonucleotide-texaphyrin metal complex conjugate where n is 1-7. 20. The method of claim 2 where R j is (CH 2 ) 2 CH 2 OH, R 2 and R 3 are CH 2 CH 3 , R 4 is CH3, R5 is 0(CH 2 CH 2 0) 2 CH 2 CH 2 OCH 3 , and ^ is a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group. 21. The method of claim 20 wherein Rg is 0(CH 2 ) n C0- oligonucleotide where n is 1-7. 22. The method of claim 17, 19 or 21 wherein n is 1 or 3. 23. The method of claim 2 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and R are CH 2 CH3, R 4 is CH3, R5 is a catalytic group or a couple to a catalytic group, and Rg is a site-directed molecule or a couple to a site-directed molecule. 24. The method of claim 2 wherein R j -Rg are as in Table 1 for texaphyrins A1-A29. 25. The method of claim 1, 2, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 wherein the metal is a lanthanide cation. 26. The method of claim 1, 2, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 wherein the metal is Eu(III) or Dy(III) . where: M is a divalent metal cation selected from the group consisting of Ca +2 , Mn +2 , Co +2 , Ni +2 , Zn +2 , Cd +2 , Hg +2 , Fe +2 , Sm +2 and U0 +2 or a trivalent metal cation selected from the group consisting of Mn +3 , Co +3 , Ni +3 , Fe +3 , Ho +3 , Ce +3 , Y +3 , In +3 , Pr +3 , Nd +3 , Sm +3 , Eu +3 , Gd +3 , Tb +3 , Dy +3 , Er +3 , Tm +3 , Yb +3 , Lu +3 , La +3 , and U +3 ; R j , R 2 , R3, R 4 , R5 and Rg are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, saccharide, carboxyalkyl, carboxyamidealkyl, a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group, and at least one of R R 2 , R3, R 4 , R5 and Rg is a site- directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group; and N is an integer less than or equal to 2. 28. The texaphyrin of claim 27 wherein the catalytic group is imidazole, guanidine, an amino acid, an amino acid derivative, a polyamino acid, an amino-substituted saccharide or a texaphyrin metal complex. 29. The texaphyrin of claim 27 wherein the site-directed molecule is an oligonucleotide, a hormone, an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule. 30. The texaphyrin of claim 27 wherein the site-directed molecule is an oligonucleotide. 31. The texaphyrin of claim 27 wherein the site-directed molecule is an oligodeoxyribonucleotide. 32. The texaphyrin of claim 27 wherein the site-directed molecule is an oligonucleotide conjugated to a catalytic group. 33. The texaphyrin of claim 32 wherein the catalytic group is a texaphyrin metal complex. 34. The texaphyrin of claim 30 wherein the oligonucleotide has complementary binding affinity for oncogenes. 35. The texaphyrin of claim 30 wherein the oligonucleotide has complementary binding affinity for RNA in a region proximal to a phosphate ester bond to be hydrolyzed. 36. The texaphyrin of claim 30 wherein the oligonucleotide has complementary binding affinity for a targeted intracellular mRNA. 37. The texaphyrin of claim 27 wherein one of R3, R5 and Rfl is an oligonucleotide or a couple to an oligonucleotide. 38. The texaphyrin of claim 27 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and R3 are CH 2 CH3, R 4 is CH3, R 5 is a site-directed molecule, a catalytic group, or a couple to a site- directed molecule or to a catalytic group and Rg is H. 39. The texaphyrin of claim 38 wherein R5 is 0(CH 2 ) n C0- oligonucleotide where n is 1-7. 40. The texaphyrin of claim 27 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and 3 are CH 2 CH3, R 4 is CH3, R5 is a (couple) t -site directed molecule-catalytic group conjugate where t is zero or 1 and Rg is H. 41. The texaphyrin of claim 40 wherein 5 is 0(CH 2 ) n CO- oligonucleotide-texaphyrin metal complex conjugate where n is 1-7. 42. The texaphyrin of claim 27 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and R3 are CH 2 CH3, R 4 is CH3, R5 is 0(CH 2 CH 2 0) 2 CH 2 CH 2 OCH3, and Rg is a site-directed molecule, a catalytic group, or a couple to a site-directed molecule or to a catalytic group. 43. The texaphyrin of claim 42 wherein Rg is 0(CH 2 ) n CO- oligonucleotide where n is 1-7. 44. The texaphyrin of claim 39, 41 or 43 wherein n is 1 or 3. 45. The texaphyrin of claim 27 wherein R j is (CH 2 ) 2 CH 2 OH, R 2 and R3 are CH 2 CH3, R 4 is CH3, R5 is a catalytic group or a couple to a catalytic group, and Rg is a site-directed molecule or a couple to a site-directed molecule. 46. The texaphyrin of claim 27 wherein R j -Rg are as in Table 1 for any one of texaphyrins A3-A6, A8-A12, A19, A21, A22 and A24-29. 47. The texaphyrin of claim 27, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46 wherein the metal is a lanthanide cation. 48. The texaphyrin of claim 27, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46 wherein the metal is Eu(III) or Dy(III)

Inventors: DOW WILLIAM C, HEMMI GREGORY W, IVERSON BRENT, KRAL VLADIMIR A, MAGDA DARREN, MILLER RICHARD A, MODY TARAK, ROSS KEVIN L, SESSLER JONATHAN L, SMITH DANIEL A, WRIGHT MEREDITH, DOW, WILLIAM, C., HEMMI, GREGORY, W., IVERSON, BRENT, KRAL, VLADIMIR, A., MAGDA, DARREN, MILLER, RICHARD, A., MODY, TARAK, ROSS, KEVIN, L., SESSLER, JONATHAN, L., SMITH, DANIEL, A., WRIGHT, MEREDITH
Applicants: PHARMACYCLICS INC, UNIV TEXAS, BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM, DOW, WILLIAM, C., HEMMI, GREGORY, W., IVERSON, BRENT, KRAL, VLADIMIR, A., MAGDA, DARREN, MILLER, RICHARD, A., MODY, TARAK, PHARMACYCLICS, INC., ROSS, KEVIN, L., SESSLER, JONATHAN, L., SMITH, DANIEL, A., WRIGHT, MEREDITH
Application year: 1994
Main classification: C07D487
IPC codes: A61K41, A61K47, A61K49, B01J31, C07B61, C07D487, C07F9, C07H21